Phosphonosulfonate compounds, pharmaceutical compositions, and methods for treating abnormal calcium and phosphate metabolism

ABSTRACT

The present invention relates to phosphonsulfonates and the pharmaceutically-acceptable salts and esters thereof, having the following structure according to formula (I): ##STR1## The present invention further relates to pharmaceutical compositions containing a safe and effective amount of a compound of the present invention, and pharmaceutically-acceptable excipients. Finally, the present invention relates to methods for treating or preventing pathological conditions characterized by abnormal calcium and phosphate metabolism in humans or other mammals, including treating or preventing osteoporosis and arthritis, especially rheumatoid arthritis and osteoarthritis. This method comprises administering to a human or other mammal in need of such treatment of a safe and effective amount of a compound or composition of the present invention.

This is a continuation-in-part of U.S. patent application Ser. Nos.07/890,885, (abandoned) 07/891,487, (abandoned) 07/891,355, (abandoned)07/891,490, (abandoned) 07/890,886, (abandoned) and 07/891,309,(abandoned) all filed May 29, 1992.

BACKGROUND OF THE INVENTION

This invention relates to novel phosphonosulfonate compounds. Thisinvention further relates to pharmaceutical compositions containingthese novel compounds, as well as to methods for treating or preventingmetabolic bone disorders characterized by abnormal calcium and phosphatemetabolism by utilizing a compound or pharmaceutical composition of thepresent invention. Specifically, this invention relates to methods fortreating or preventing osteoporosis, or arthritis, especially rheumatoidarthritis and osteoarthritis, by utilizing a compound or pharmaceuticalcomposition of the present invention.

A number of pathological conditions which can afflict humans and warmblooded animals involve abnormal calcium and phosphate metabolism. Suchconditions may be divided into two broad categories:

(1) Conditions which are characterized by anomalous mobilization ofcalcium and phosphate leading to general or specific bone loss, such asosteoporosis and Paget's disease, or excessively high calcium andphosphate levels in the fluids of the body, such as hypercalcemia oftumor origin. Such conditions are sometimes referred to herein aspathological hard tissue demineralizations.

(2) Conditions which cause or result from deposition of calcium andphosphate anomalously in the body, such as arthritis, includingrheumatoid arthritis and osteoarthritis. These conditions are sometimesreferred to herein as pathological calcifications.

The first category includes the most common metabolic bone disorder,osteoporosis; osteoporosis is a condition in which bone hard tissue islost disproportionately to the development of new hard tissue.Osteoporosis can be generally defined as the reduction in the quantityof bone, or the atrophy of skeletal tissue. Marrow and bone spacesbecome larger, fibrous binding decreases, and compact bone becomesfragile. Osteoporosis can be subclassified as menopausal, senile,drug-induced (e.g. adrenocorticoid, as can occur in steroid therapy);disease-induced (arthritic and tumor), etc.; however, the manifestationsare essentially the same.

In general, there are two types of osteoporosis: primary and secondary."Secondary osteoporosis" is the result of a separate disease process oragent. However, approximately 90% of all osteoporosis cases are "primaryosteoporosis". Such primary osteoporosis includes postmenopausalosteoporosis, disuse osteoporosis, age-associated osteoporosis(affecting a majority of individuals over the age of 70 to 80), andidiopathic osteoporosis affecting middle-aged and younger men and women.

For some osteoporotic individuals, the loss of bone tissue issufficiently great so as to cause mechanical failure of the bonestructure. Bone fractures often occur, for example, in the hip and spineof women suffering from postmenopausal osteoporosis. Kyphosis(abnormally increased curvature of the thoracic spine) may also result.

The mechanism of bone loss in osteoporotics is believed to involve animbalance in the process of "bone remodeling". Bone remodeling occursthroughout life, renewing the skeleton and maintaining the strength ofbone. This remodeling involves the erosion and filling of discrete siteson the surface of bones, by an organized group of cells called "basicmulticellular units" or "BMUs". BMUs primarily consist of "osteoclasts","osteoblasts", and their cellular precursors. In the remodeling cycle,bone is resorbed at the site of an "activated" BMU by an osteoclast,forming a resorption cavity. This cavity is then filled with bone by anosteoblast.

Normally, in adults, the remodeling cycle results in a small deficit inbone, due to incomplete filling of the resorption cavity. Thus, even inhealthy adults, age-related bone loss occurs. However, in osteoporotics,there may be an increase in the number of BMUs that are activated. Thisincreased activation accelerates bone remodeling, resulting inabnormally high bone loss.

Although its etiology is not fully understood, there are many riskfactors thought to be associated with osteoporosis. These include lowbody weight, low calcium intake, physical inactivity, and estrogendeficiency.

Current osteoporosis treatment consists primarily of calcium andestrogen administration.

In addition to osteoporosis, bone loss can result from arthritis,including rheumatoid arthritis and osteoarthritis. Rheumatoid arthritisis a chronic, systemic and particular inflammatory disordercharacterized by weakening of the joint capsules and ligaments, followedby destruction of cartilage, ligaments, tendon and bone, and a decreasein viscosity and other alterations in the synovial fluid. Rheumatoidarthritis symptoms include systemic weakness, fatigue, localized pain,stiffness and weakness and swelling and deformation of the joints of thebody. Rheumatoid arthritis is most common in women in the fourth tosixth decade of life.

Osteoarthritis is an inherently non-inflammatory disorder of the movablejoints characterized by deterioration and abrasion of articularcartilage, as well as by formation of new bone at the joint surface. Asosteoarthritis progresses, the surface of the articular cartilage isdisrupted and wear particles gain access to the synovial fluid which inturn stimulates phagocytosis by macrophage cells. Thus, an inflammatoryresponse is eventually induced in osteoarthritis. Common clinicalsymptoms of osteoarthritis include cartilaginous and bony enlargementsof the finger joints and stiffness on awakening and painful movement.

A variety of polyphosphonic acid derivatives have been proposed for usein the treatment and prophylaxis of diseases involving abnormal calciumand phosphate metabolism. For example, numerous references allincorporated by reference herein, disclose compositions containingpolyphosphonates, in particular bisphosphonates, such asethane-1-hydroxy-1,1diphosphonic acid ("EHDP"), and their use ininhibiting anomalous deposition and mobilization of calcium andphosphate in animal tissue: U.S. Pat. No. 3,683,080, issued Aug. 8, 1972and U.S. Pat. No. 4,230,700, issued Oct. 28, 1980, both to Francis, andU.S. Pat. No. 4,868,164 to Ebetino, issued Sep. 19, 1989. Numerous otherreferences describe substituted phosphonic acids useful for thetreatment of osteoporosis and/or arthritis, and are hereby incorporatedby reference herein: U.S. Pat. No. 5,071,840 to Ebetino, et al, issuedDec. 10, 1991, U.S. Pat. No. 4,868,164, to Ebetino, et al., issued Sep.19, 1989; U.S. Pat. No. 5,104,863, to Benedict, et al., issued Apr. 14,1992; U.S. Pat. No. 4,267,108, to Blum et al., issued May 12, 1981; U.S.Patent to Breliere, et al., issued May 24, 1988; U.S. Pat. No. 4,876,247to Barbier, et al., issued Oct. 24, 1989; European Patent ApplicationPublication No. 100,718, of Breliere S. A., published Feb. 15, 1984;European Patent Application Publication No. 170,228, of BoehfingerMannheim GmbH, published Feb. 5, 1986; European Patent ApplicationPublication No. 186,405, of Benedict and Perkins, published Jul. 2,1986; European Patent Application Publication No. 298,553, of Ebetino,published Jan. 11, 1989; U.S. Pat. No. 4,754,993, to Bosies, et al.,issued Nov. 15, 1988; U.S. Pat. No. 4,939,130 to Jaeggi, et al., issuedJul. 3, 1990; U.S. Pat. No. 4,971,958 to Bosies, et al., issued Nov. 20,1990; WO 90/12017 to Dunn, et al., published Oct. 18, 1990; WO 91/10646to Youssefyeh, R., et al., published Jul. 25, 1991; AU-A-26738/88 toJaeggi, K. A., publication date Jun. 15, 1989; AU-A45467/89 ofCiba-Geigy, publication date May 31, 1990.

A limited number of phosphonosulfonate-containing compounds aredisclosed in the literature. See for example, U.S. Pat. No. 4,032,521,to Christiansen et al., issued Jun. 28, 1977; PTC Patent Publication90/07480, by King et al., published Jul. 12, 1990; Great Britain PatentPublication No. 2,248,831, by Doyle et al., published Apr. 22, 1992, andPCT Patent Publication 91/12822, by Erfinder, published Sep. 5, 1991intermediates. None of these references suggest the utility ofphosphonosulfonate compounds, useful in preventing and treating bonemetabolism disorders.

It has been surprisingly discovered that the compounds of the presentinvention, having a phosphonosulfonate moiety, may have potent boneantiresorptive activity and therapeutic utility in treating osteoporosisand/or arthritis. Moreover, these compounds have reduced bone affinitycompared with bisphosphonates. This reduced bone affinity may decreaseside effects generally associated with the high bone affinitybisphosphonates. Such side effects include inhibition of bone formationand inhibition of bone remodeling activation frequency.

Certain compounds of the present invention contain a quaternary nitrogenmoiety. These compounds exhibit unusual solubility properties. Thus, thequaternary nitrogen-containing phosphonosulfonate compounds of thepresent invention may be more readily orally absorbed. Increased oralabsorption allows for improved therapeutic effect at lower doses. Lowerdoses are generally preferable because undesirable side effects aredecreased.

It is therefore an object of the present invention to provide a newpotent class of compounds which are potent bone resorption inhibitingagents useful in osteoporosis therapy and anti-arthritic agents usefulin the treatment of arthritis, especially osteoarthritis and rheumatoidarthritis. It is a further object of the present invention to providepharmaceutical compositions useful for the treatment and prophylaxis ofabnormal calcium and phosphate metabolism. In addition, it is an objectof the present invention to provide methods for treating or preventingdiseases characterized by abnormal calcium and phosphate metabolism inhumans or other mammals.

These and other objects of the present invention will become apparentfrom the detailed disclosure of the present invention providedhereinafter.

SUMMARY OF THE INVENTION

The present invention relates to phosphonosulfonates and thepharmaceutically-acceptable salts and esters thereof, having a structureaccording to formula (I): ##STR2## wherein

(A)

(1) A is selected from the group consisting of hydrogen; halogen; SR¹ ;R² SR¹ ; amino; hydroxy; and substituted or unsubstituted C₁ -C₈ alkyl;

(2) B is

(a) --NH₂ ;

(b) a saturated or unsaturated C₁ -C₁₅ alkyl chain substituted with oneor more substituents selected from the group consisting of --R³ N(R⁴)₂ ;--R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴; and --R³ C(O)N(R⁴)₂ ;

(c) a substituted or unsubstituted, saturated or unsaturated heteroalkylchain having from 2 to 15 chain atoms, where one or more of said chainatoms is nitrogen;

(d) a saturated or unsaturated heteroalkyl chain having from 2 to 15chain atoms, where one or more of said chain atoms is selected from Sand O; and where said heteroalkyl chain is substituted with one or moresubstituents selected from the group consisting of --R³ N(R⁴)₂ ; --R³--N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ;and --R³ C(O)N(R⁴)₂ ; or

(e) R⁶ --L-- where

(i) L is selected from the group consisting of nil; N; --N(R⁵)₂ +; S; O;a substituted or unsubstituted, saturated or unsaturated C₁ -C₁₅ alkylchain; and a substituted or unsubstituted, saturated or unsaturatedheteroalkyl chain having from 2 to 15 chain atoms, where one or more ofsaid chain atoms is N, S, or O; and

(ii) R⁶ is selected from the group consisting of saturated monocyclic orpolycyclic carbocyclic rings; unsaturated monocyclic or polycycliccarbocyclic tings; saturated monocyclic or polycyclic heterocyclicrings; and unsaturated monocyclic or polycyclic heterocyclic rings;wherein R⁶ may be substituted with one or more substituentsindependently selected from the group consisting of hydrogen; --R³ SR¹ ;substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴; arylalkyl; nitro; substituted or unsubstituted aryl; and hydroxy; and

(3)

(a) R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; --C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R⁷)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or substituted or unsubstituted C₁ -C₈alkyl;

(b) R² is substituted or unsubstituted C₁ -C₈ alkyl;

(c) R³ is selected from the group consisting of nil and substituted orunsubstituted C₁ -C₈ alkyl;

(d) R⁴ is independently selected from the group consisting of hydrogen;substituted or unsubstituted C₁ -C₈ alkyl; and --R² SR¹ ; and

(e) R⁵ is independently selected from the group consisting ofsubstituted or unsubstituted C₁ -C₁₅ alkyl; substituted or unsubstitutedphenyl; benzyl; and --R² SR¹ ;

or

A and B are covalently linked together with C* to form a monocyclic orbicyclic ting having the following structure: ##STR3## where (1) W is asubstituted or unsubstituted, saturated or unsaturated carbocyclic ringcomprising C*, X, and X', said carbocyclic ting having a total of from 3to 6 ring carbon atoms; or a substituted or unsubstituted, saturated orunsaturated heterocyclic ring comprising C*, X, and X', saidheterocyclic ring having a total of from 4 to 6 ring atoms, where one ormore of said ring atoms is N, O, or S;

(2) V is nil; a substituted or unsubstituted, saturated or unsaturatedcarbocyclic ring comprising X and X', said carbocyclic ring having atotal of from 3 to 8 ring carbon atoms; or a substituted orunsubstituted, saturated or unsaturated heterocyclic ring comprising Xand X', said heterocyclic ring having a total of from 3 to 8 ring atoms,where one or more of said ring atoms is N, O, or S; and

(3) X and X' are independently N or C; except that if neither V nor W isa nitrogen containing heterocycle, then at least one of V or W issubstituted with one or more substituents selected from the groupconsisting of --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;

and wherein R is selected from the group consisting of hydrogen, loweralkyl, lower acyloxyalkyl, aminocarbonyloxyalkyl, pivaloyloxymethyl,lactonyl, lower alkoxyacyloxyalkyl, alkoxyalkyl, choline and acylaminoalkyl.

The present invention further relates to pharmaceutical compositionscomprising a safe and effective amount of a phosphonosulfonate, or apharmaceutically-acceptable salt or ester thereof. Finally, the presentinvention relates to methods for treating or preventing pathologicalconditions characterized by abnormal calcium and phosphate metabolism inhumans or other mammals. These methods comprise administering to a humanor other mammal in need of such treatment a safe and effective amount ofa compound or a composition of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

Phosphonosulfonate Compounds

The novel compounds of the present invention are phosphonosulfonates andthe pharmaceutically-acceptable salts and esters thereof, having astructure according to formula (I): ##STR4## wherein

(A)

(1) A is selected from the group consisting of hydrogen; halogen; SR¹ ;R² SR¹ ; amino; hydroxy; and substituted or unsubstituted C₁ -C₈ alkyl;

(2) B is

(a) --NH₂ ;

(b) a saturated or unsaturated C₁ -C₁₅ alkyl chain substituted with oneor more substituents selected from the group consisting of --R³ N(R⁴)₂ ;--R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴; and --R³ C(O)N(R⁴)₂ ;

(c) a substituted or unsubstituted, saturated or unsaturated heteroalkylchain having from 2 to 15 chain atoms, where one or more of said chainatoms is nitrogen;

(d) a saturated or unsaturated heteroalkyl chain having from 2 to 15chain atoms, where one or more of said chain atoms is selected from Sand O; and where said heteroalkyl chain is substituted with one or moresubstituents selected from the group consisting of --R³ N(R⁴)₂ ; --R³--N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ;and --R³ C(O)N(R⁴)₂ ; or

(e) R⁶ --L-- where

(i) L is selected from the group consisting of nil; N; --N(R⁵)₂ +; S; O;a substituted or unsubstituted, saturated or unsaturated C₁ -C₁₅ alkylchain; and a substituted or unsubstituted, saturated or unsaturatedheteroalkyl chain having from 2 to 15 chain atoms, where one or more ofsaid chain atoms is N, S, or O; and

(ii) R⁶ is selected from the group consisting of saturated monocyclic orpolycyclic carbocyclic rings; unsaturated monocyclic or polycycliccarbocyclic rings; saturated monocyclic or polycyclic heterocyclicrings; and unsaturated monocyclic or polycyclic heterocyclic rings;wherein R⁶ may be substituted with one or more substituentsindependently selected from the group consisting of hydrogen; --R³ SR¹ ;substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴; arylalkyl; nitro; substituted or unsubstituted aryl; and hydroxy; and

(3)

(a) R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; --C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R⁷)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or substituted or unsubstituted C₁ -C₈alkyl;

(b) R² is substituted or unsubstituted C₁ -C₈ alkyl;

(c) R³ is selected from the group consisting of nil and substituted orunsubstituted C₁ -C₈ alkyl;

(d) R⁴ is independently selected from the group consisting of hydrogen;substituted or unsubstituted C₁ -C₈ alkyl; and --R² SR¹ ; and

(e) R⁵ is independently selected from the group consisting ofsubstituted or unsubstituted C₁ -C₁₅ alkyl; substituted or unsubstitutedphenyl; benzyl; and --R² SR¹ ;

or

(B) A and B are covalently linked together with C* to form a monocyclicor bicyclic ring having the following structure: ##STR5## where (1) W isa substituted or unsubstituted, saturated or unsaturated carbocyclicring comprising C*, X, and X', said carbocyclic ring having a total offrom 3 to 6 ring carbon atoms; or a substituted or unsubstituted,saturated or unsaturated heterocyclic ring comprising C*, X, and X',said heterocyclic ring having a total of from 4 to 6 ring atoms, whereone or more of said ring atoms is N, O, or S;

(2) V is nil; a substituted or unsubstituted, saturated or unsaturatedcarbocyclic ring comprising X and X', said carbocyclic ring having atotal of from 3 to 8 ring carbon atoms; or a substituted orunsubstituted, saturated or unsaturated heterocyclic ring comprising Xand X', said heterocyclic ring having a total of from 3 to 8 ring atoms,where one or more of said ring atoms is N, O, or S; and

(3) X and X' are independently N or C; except that if neither V nor W isa nitrogen containing heterocycle, then at least one of V or W issubstituted with one or more substituents selected from the groupconsisting of --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;

and wherein R is selected from the group consisting of hydrogen, loweralkyl, lower acyloxyalkyl, aminocarbonyloxyalkyl, pivaloyloxymethyl,lactonyl, lower alkoxyacyloxyalkyl, alkoxyalkyl, choline and acylaminoalkyl.

Definitions and Usage of Terms

The following is a list of definitions for terms used herein.

"Heteroatom" is a nitrogen, sulfur, or oxygen atom. Groups containingone or more heteroatoms may contain different heteroatoms.

"Alkyl" is an unsubstituted or substituted, straight-chain or branched,saturated or unsaturated hydrocarbon chain, said hydrocarbon chain maybe saturated, having 1 to 15 carbon atoms, and preferably, unlessotherwise stated, from 1 to 4 carbon atoms; said hydrocarbon chain maybe unsaturated, having 2 to 8 carbon atoms, and preferably, unlessotherwise stated, 2 to 4 carbon atoms. Accordingly, the term "alkyl", asused herein, encompasses alkenyl hydrocarbon unsaturated chains havingat least one olefinic double bond and alkynyl hydrocarbon unsaturatedchains having at least one triple bond. Preferred alkyl groups include,but are not limited to, methyl, ethyl, propyl, isopropyl, and butyl.

"Heteroalkyl" is an unsubstituted or substituted, saturated orunsaturated, straight-chain or branched heteroalkyl chain, said chainhaving from 2 to 15, preferably 2 to 8 members, and comprising at leastone carbon atom and at least one heteroatom. The term "heteroalkyl", asused herein, encompasses alkenyl heteroalkyl unsaturated chains havingat least one olefinic double bond and alkynyl heteroalkyl unsaturatedchains having at least one triple bond.

"Carbocyclic ring" or "Carbocycle" as used herein is an unsubstituted orsubstituted, saturated, unsaturated or aromatic, hydrocarbon ring.Carbocycles may be monocyclic or polycyclic: Monocyclic rings generallycontain from 3 to 8 atoms, preferably 5 to 8 atoms. Polycyclic ringscontaining two rings contain 6-16, preferably 10 to 12, atoms and thosewith three rings generally contain 13 to 17, preferably 14 to 15, atoms.

"Heterocyclic ring" or "Heterocycle" as used herein is an unsubstitutedor substituted, saturated, unsaturated or aromatic ring comprised ofcarbon atoms and one or more heteroatoms in the ring. Heterocyclic ringsmay be monocyclic or polycyclic. Monocyclic rings generally contain from3 to 8 atoms, preferably 5 to 7 atoms. Polycyclic ring systemsconsisting of two rings generally contain 6 to 16, preferably from 10 to12 atoms. Polycyclic ring systems consisting of three rings generallycontain 13 to 17 atoms, preferably 14 to 15 atoms. Unless otherwisestated the heteroatoms may be independently chosen from nitrogen,sulfur, and oxygen. Unsaturated, non-aromatic heterocycles include, butare not limited to, substituted or unsubstituted thiophene, substitutedor unsubstituted oxathiazole, substituted or unsubstituted pyrans, andsubstituted or unsubstituted furans.

"Aryl" is an aromatic carbocyclic ring. Preferred aryl groups include,but are not limited to, phenyl, tolyl, xylyl, cumenyl, and naphthyl.

"Heteroaryl" is an aromatic heterocyclic ring. Preferred heteroarylgroups include, but are not limited to, thienyl, furyl, pyrrolyl,pyridinyl, pyrazinyl, oxazolyl, thiazolyl, quinolinyl, pyrimidinyl, andtetrazolyl.

"Alkoxy" is an oxygen atom having a hydrocarbon chain substituent, wherethe hydrocarbon chain is an alkyl or alkenyl (e.g., --O-alkyl or--O-alkenyl). Preferred alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy, and alkyloxy.

"Hydroxyalkyl" is a substituted hydrocarbon chain which has a hydroxysubstituent (e.g., --OH), and may have other substituents. Preferredhydroxyalkyl groups include, but are not limited to, hydroxyethyl andhydroxypropyl.

"Carboxyalkyl" is a substituted hydrocarbon chain which has a carboxysubstituent (e.g. --COOH) and may have other substituents. Preferredcarboxyalkyl groups include carboxymethyl, carboxyethyl, and their acidsand esters.

"Aminoalkyl" is a hydrocarbon chain (e.g. alkyl) substituted with anamine moiety (e.g., NH-alkyl-), such as aminomethyl alkyl.

"Alkylamino" is an amino moiety having one or two alkyl substituents(e.g., --N-alkyl), such as dimethylamino.

"Alkenylamino" is an amino moiety having one or two alkenyl substituents(e.g., --N-alkenyl).

"Alkynylamino" is an amino moiety having one or two alkynyl substituents(e.g., --N-alkynyl).

"Alkylimino" is an imino moiety having one or two alkyl substituents(e.g., --N-alkyl-).

"Arylalkyl" is an alkyl moiety substituted with an aryl group. Preferredarylalkyl groups include benzyl and phenylethyl.

"Arylamino" is an amine moiety substituted with an aryl group (e.g.,--NH-aryl).

"Aryloxy" is an oxygen atom having an aryl substituent (e.g., --O-aryl).

"Acyl" or "carbonyl" is a carbon to oxygen double bond, e.g. R--C(═O).Preferred acyl groups include, but are not limited to, acetyl,propionyl, butanoyl and benzoyl.

"Acyloxy" is an oxygen atom having an acyl substituent (e.g., --O-acyl);for example, --O--C(═O)-alkyl.

"Acylamino" is an amino moiety having an acyl substituent (e.g.,--N-acyl); for example, --NH--(C═O)-alkyl.

"Halo", "halogen", or "halide" is a chloro, bromo, fluoro, or iodo atomradical. Chloro, bromo, and fluoro are preferred halides.

Also, as referred to herein, a "lower" hydrocarbon moiety (e.g., "lower"alkyl) is a hydrocarbon chain comprised of from, unless otherwisestated, 1 to 6, preferably from 1 to 4, carbon atoms.

As used herein the term "thio-substituent" (SR¹ or R² SR¹) includesthiols --SH! where R¹ ═H; thioesters --SC(O)R⁷ ! where R¹ ═C(O)R⁷ ;dithioesters --SC(S)R⁷ ! where R¹ ═C(S)R⁷ ; thiocarbamates --SC(O)N(R⁷)₂! where R¹ ═C(O)N(R⁷)₂ ; dithiocarbamates --SC(S)N(R⁷)₂ ! where R¹═C(S)N(R⁷)₂ ; thiocarbonates --SC(O)OR⁷ ! where R¹ ═C(O)OR⁷ ; anddithiocarbonates --SC(S)OR⁷ ! where R¹ ═C(S)OR⁷. R⁷ is a hydrogen or C₁-C₈ alkyl. Any of the SR¹ substituents may themselves be substitutedwith an R² moiety, where R² is a substituted or unsubstituted C₁ -C₈alkyl. Accordingly, additional thio-substituents denoted by R² SR¹ arealkylthiols, alkylthioesters, alkyldithioesters, alkylthiocarbamates,alkyldithiocarbamates, alkylthiocarbonates and alkyl dithiocarbonates.

The term "phosphonosulfonate", as used herein, relates to compounds thathave a phosphonate group (PO₃ H₂) and a sulfonate group (SO₃ H) attachedto the same carbon atom.

A "pharmaceutically-acceptable" salt is a cationic salt formed at anyacidic (e.g., carboxyl) group, or an anionic salt formed at any basic(e.g., amino) group. Many such salts are known in the art, as describedin World Patent Publication 87/05297, Johnston et al., published Sep.11, 1987, hereby incorporated by reference herein. Preferred cationicsalts include the alkali-metal salts (such as sodium and potassium), andalkaline earth metal salts (such as magnesium and calcium). Preferredanionic salts include the halides (such as chloride), acetate andphosphate salts.

A "biohydrolyzable ester" is an ester of the phosphonosulfonatecompounds that does not interfere with the therapeutic activity of thecompounds, or that is readily metabolized by a human or other mammal.Many such esters are known in the art, as described in World PatentPublication 87/05297, Johnston et al., published Sep. 11, 1987, andhereby incorporated by reference herein. Such esters include lower alkylesters, lower acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl,aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl esters),lactonyl esters (such as phthalidyl and thiophthalidyl esters), loweralkoxyacyl oxyalkyl esters (such as methoxycarbonyloxymethyl,ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters),alkoxyalkyl esters, choline esters, and acylamino alkyl esters (such asacetamidomethyl esters). While the preceding esters are preferred, anypharmaceutically-acceptable ester is deemed to be within the scope ofthe present invention.

As defined above and as used herein, substituent groups may themselvesbe substituted. Such substitution may be with one or more substituents.Such substituents include, but are not limited to, those listed in C.Hansch and A. Leo, Substituent Constants for Correlation Analysis inChemistry and Biology (1979), hereby incorporated by reference herein.Preferred substituents include, but are not limited to, alkyl, alkenyl,alkoxy, hydroxy, oxo, thioxo (--C(═S)--); amino, aminoalkyl (e.g.aminomethyl, etc.), cyano, quaternary amino, quaternary aminoalkyl,amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl (e.g. carboethoxy,etc.), thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl(e.g., piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, etc.),imino, hydroxyalkyl, aryloxy, arylalkyl, alkynyl and combinationsthereof. Particularly preferred substituents include, but are notlimited to, amino, aminoalkyl, quaternary amino, amidino, quaternaryaminoalkyl and amidinoalkyl.

Also, as used in defining the structure of the compounds of thisinvention, a particular radical may be defined for use as a substituent,in multiple locations. As used herein, such a radical is independentlyselected each time it is used.

In formula (I), when A is halogen, it is preferably chlorine or bromine.When A is a sulfur containing moiety, the preferred moiety is SR¹, whereR¹ is preferably hydrogen or acyl. Particularly preferred is where R¹ ishydrogen. Preferred A moieties are amino and hydroxy. Particularlypreferred is where A is hydroxy. When B is saturated or unsaturated C₁-C₁₅ alkyl, the alkyl chain must be substituted with one or moresubstituents selected from the group consisting of --R³ N(R⁴)₂ ; R³--N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ;and --R³ C(O)N(R⁴)₂. Preferably the required substituent is selectedfrom --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ;and --R³ N(R⁴)C(N)R⁴. Most preferred is where the required substituentis selected from --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; and --R³ N(R⁴)C(O)R⁴. Thealkyl chain may also be substituted with one or more substituentsselected from the group consisting of nil; --R³ SR¹ ; hydrogen;substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³O₂ CR⁴ ; halogen; --R³ C(O)R⁴ ; nitro; hydroxy; substituted orunsubstituted saturated monocyclic or polycyclic carbocyclic rings;substituted or unsubstituted unsaturated monocyclic or polycycliccarbocyclic rings; substituted or unsubstituted saturated monocyclic orpolycyclic heterocyclic rings; and substituted or unsubstitutedunsaturated monocyclic or polycyclic heterocyclic rings. Preferred areC₁ -C₈ alkyl chains.

When B is saturated or unsaturated heteroalkyl having from 2 to 15atoms, where one of said atoms is a nitrogen, the heteroalkyl chain maybe substituted with one or more substituents selected from the groupconsisting of --R³ SR¹ ; hydrogen; substituted or unsubstituted C₁ -C₈alkyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; --R³ N(R⁵)₃!+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴ ; nitro; hydroxy; substituted orunsubstituted saturated monocyclic or polycyclic carbocyclic rings;substituted or unsubstituted unsaturated monocyclic or polycycliccarbocyclic rings; substituted or unsubstituted saturated monocyclic orpolycyclic heterocyclic rings; and substituted or unsubstitutedunsaturated monocyclic or polycyclic heterocyclic rings. Preferrednitrogen-containing heteroalkyl chains have from 2 to 8 chain atoms.

When B is saturated or unsaturated heteroalkyl having from 2 to 15atoms, where one of said atoms is a sulfur or oxygen, and where nonitrogen atom is in the heteroalkyl chain, then the heteroalkyl chainmust be substituted with one or more substituents selected from thegroup consisting of --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ;--R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂. The requiredsubstituent is preferably one of --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; or --R³ N(R⁴)C(N)R⁴. Most preferred iswhere the required substituent is --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; or --R³N(R⁴)C(O)R⁴. The heteroalkyl chain may also be substituted with one ormore substituents selected from the group consisting of nil; --R³ SR¹ ;hydrogen; substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ; --R³ CO₂R⁴ ; --R³ O₂ CR⁴ ; halogen; --R³ C(O)R⁴ ; nitro; hydroxy; substituted orunsubstituted saturated monocyclic or polycyclic carbocyclic rings;substituted or unsubstituted unsaturated monocyclic or polycycliccarbocyclic rings; substituted or unsubstituted saturated monocyclic orpolycyclic heterocyclic rings; and substituted or unsubstitutedunsaturated monocyclic or polycyclic heterocyclic rings. Preferrednon-nitrogen containing heteroalkyl chains have from 2 to 8 chain atoms.

When B is R⁶ --L--, the L moiety may be substituted with one or moresubstituents selected from the group consisting of --R³ SR¹ ; hydrogen;substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³O₂ CR⁴ ; --R³ N(R⁴)₂ ; --R³ N(R⁵)₂ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴; nitro; hydroxy; substituted or unsubstituted saturated monocyclic orpolycyclic carbocyclic rings; substituted or unsubstituted unsaturatedmonocyclic or polycyclic carbocyclic rings; substituted or unsubstitutedsaturated monocyclic or polycyclic heterocyclic rings; and substitutedor unsubstituted unsaturated monocyclic or polycyclic heterocyclicrings. The L moiety is preferably a nitrogen atom (including quaternarynitrogen), a nitrogen containing heteroalkyl, or alkyl. Where L is aheteroalkyl chain or an alkyl chain, the chain preferably has 1 to 8chain atoms.

The R⁶ moiety may be a saturated or unsaturated, monocyclic orpolycyclic carbocycle or heterocycle. Where R⁶ is a monocycliccarbocycle, it is preferably cycloheptyl or cyclohexyl. When R⁶ is amonocyclic heterocycle, preferred are six-membered nitrogen containingsrings including pyridine, pyrimidine, piperidine. Also preferred arethose six-membered heterocycles having a quaternary nitrogen ring atom,including pyridinium, pyrimidinium, piperidinium, and pyrazolium.Preferred monocyclic heterocycles also include five-membered nitrogencontaining heterocycles, including imidazol, pyrrole, and pyrrolidine.Also preferred are five-membered heterocycles having a quaternarynitrogen ring atom, including imidazolium, pyrrolium, and pyrrolidinium.Where R⁶ is a polycycle, preferred are polycyclic heterocycles having asix-membered ring fused to another six-membered ring and those having asix-membered ring fused to a five-membered ring. Preferred polycyclicheterocycles include those having a quaternary ring nitrogen atom.Particularly preferred R⁶ moieties include pyridyl and cycloheptyl.

The R³ moiety is preferably nil.

The R⁴ moiety is preferably hydrogen.

The R⁵ moiety comprises a nitrogen atom bound to three carbon-containingmoieties. The R⁵ moiety is substituted on a carbon atom of anothermoiety, thus providing a quaternary amine group. As indicated in thegeneral structure, the quaternary amine moiety may be a substituent onany of the chain or cyclic moieties described above.

B is preferably a heteroalkyl chain having at least one nitrogen chainatom, or R⁶ --L--. Particularly preferred B moieties are R⁶ --L--.

According to formula (I), A and B may, together with C*, X and X', forma cyclic structure. Preferred cyclic structures are those where V is aheterocycle having at least one ring nitrogen atom. This ring nitrogenatom may be a secondary, tertiary or quaternary amine. Where neither Vnor W is a heterocycle having at least one ring nitrogen atom, then atleast one of V or W must be substituted with one or more moietiesselected from the group consisting of --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³--N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³C(O)N(R⁴)₂. In addition to the above requirement, each of V and W may besubstituted with one or more substituents selected from the groupconsisting of --R³ SR¹ ; hydrogen; substituted or unsubstituted C₁ -C₈alkyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; halogen; --R³ C(O)R⁴ ;hydroxy; substituted or unsubstituted arylalkyl; nitro; andunsubstituted or substituted aryl.

Preferred compounds of the present invention are phosphono-sulfonatesand the pharmaceutically-acceptable salts and esters thereof, having ageneral structure according to formula (I): ##STR6## wherein

(A)

(1) A is selected from the group consisting of amino and hydroxy; and

(2) B is ##STR7## wherein (a) m is an integer from 0 to 10; n is aninteger from 0 to 10; and m+n is an integer from 0 to 10;

(b) R⁸ is independently selected from the group consisting of nil; --R³SR¹ ; hydrogen; substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ;--R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; --R³ N(R⁵)₃ !+; --R³N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ;halogen; --R³ C(O)R⁴ ; nitro; hydroxy; substituted or unsubstitutedsaturated monocyclic or polycyclic carbocyclic rings; substituted orunsubstituted unsaturated monocyclic or polycyclic carbocyclic rings;substituted or unsubstituted saturated monocyclic or polycyclicheterocyclic rings; and substituted or unsubstituted unsaturatedmonocyclic or polycyclic heterocyclic rings;

(c) R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; --C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R⁷)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or substituted or unsubstituted C₁ -C₈alkyl;

(d) R³ is selected from the group consisting of nil and substituted orunsubstituted C₁ -C₈ alkyl;

(e) R⁴ is independently selected from the group consisting of hydrogen;substituted or unsubstituted C₁ -C₈ alkyl; and --R² SR¹ ;

(f) R⁵ is independently selected from the group consisting ofsubstituted or unsubstituted C₁ -C₁₅ alkyl; substituted or unsubstitutedphenyl; benzyl; and --R² SR¹ ;

(g) L is selected from the group consisting of nil; --N(R⁸)--; --N(R⁵)₂--!+; --S--; --O--; and --D--C(═E)--S--, where D is selected from thegroup consisting of covalent bond, O, or S, and E is O or S; and wherein

(i) when L is --N(R⁸)--, or when L is --N(R⁵)₂ --!+ and m is an integerfrom 1 to 10, R⁹ is independently selected from the group consisting ofnil; hydrogen; substituted or unsubstituted C₁ -C₁₅ alkyl; R² SR¹ ; andR¹⁰ ;

(ii) when L is --N(R⁵)₂ --!+ and m=0, R⁹ is selected from the groupconsisting of substituted or unsubstituted C₁ -C₁₅ alkyl; R² SR¹ ; andR¹⁰ ; or

(iii) when L is nil, --S--, --O--, or --D--C(═E)--S, R⁹ is R¹⁰ ;

(h) R¹⁰ is a saturated, unsaturated, or aromatic monocyclic orpolycyclic carbocycle or a saturated, unsaturated, or aromaticmonocyclic or polycyclic heterocycle containing one or more heteroatoms;where said carbocycle or heterocycle is substituted with one or more R¹¹substituents; and

(i) each R¹¹ is independently selected from the group consisting of --R³SR¹ ; hydrogen; substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴ ;--R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ;halogen; --R³ C(O)R⁴ ; hydroxy; substituted or unsubstituted arylalkyl;nitro; and unsubstituted or substituted aryl;

or

(B) A and B are covalently linked together with C* to form a monocyclicor bicyclic ring having the following structure: ##STR8## wherein (a) Aand B are independently selected from the group consisting of nil,--O--, --S--, and --NR¹² --;

(b) Q is selected from the group consisting of nil; --NR¹² --; and--N(R¹³)₂ --!+;

(c) X and X' are independently selected from C or N;

(d) each R¹² is independently selected from the group consisting of nil;--R³ SR¹ ; hydrogen; substituted or unsubstituted C₁ -C₈ alkyl; --R³ OR⁴; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³N(R⁴)C(O)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴ ; hydroxy;substituted or unsubstituted arylalkyl; nitro; and unsubstituted orsubstituted aryl; and

(e) each R¹³ is selected from the group consisting of substituted orunsubstituted C₁ -C₁₅ alkyl; substituted or unsubstituted phenyl;benzyl; and --R² SR¹ ;

(f) When Q is other than nil, k and j and k+j are integers from 0 to 5;when Q is nil, k and j and k+j are integers from 0 to 6; and

(g) p and q and p+q are independently integers from 0 to 3; except thatif Q is nil, then at least one of R¹¹ or R¹² is selected from the groupconsisting of --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;

and wherein R is selected from the group consisting of hydrogen, loweralkyl, lower acyloxyalkyl, aminocarbonyloxyalkyl, pivaloyloxymethyl,lactonyl, lower alkoxyacyloxyalkyl, alkoxyalkyl, choline and acylaminoalkyl.

Preferred phosphonosulfonate compounds of formula (I) have a nitrogencontaining heterocycle linked to the phosphonosulfonate geminal carbonvia a linking chain. Included are phosphonosulfonate compounds havingthe following general structures:

(1) ##STR9## where the nitrogen containing heterocycle is a pyridyl orpyridinium; ##STR10## where the nitrogen containing heterocycle is amonocycle other than pyridyl or pyridinium; ##STR11## where the nitrogencontaining heterocycle is a polycycle.

Also preferred are those phosphonosulfonate compounds having a nitrogencontaining heteroalkyl moiety linked to the phosphonosulfonatecontaining geminal carbon. Such compounds include those having thefollowing structure, where R⁸ and R⁹ are non-cyclic substituents:##STR12##

Also preferred are those compounds having the following structure, whereR⁹ is a cycloheptyl ring: ##STR13##

Also preferred are substituted or unsubstituted octahydrophosphonosulfono pyrindines having the general structures: ##STR14##referred to herein as unsubstituted or substitutedoctahydro-5-phosphono-5-sulfono-1-pyrindines; ##STR15## referred toherein as unsubstituted or substitutedoctahydro-5-phosphono-5-sulfono-2-pyrindines; ##STR16## referred toherein as unsubstituted or substitutedoctahydro-6-phosphono-6-sulfono-1-pyrindines;

(4) ##STR17## referred to herein as unsubstituted or substitutedoctahydro-6-phosphono-6-sulfono-2-pyrindines; ##STR18## referred toherein as octahydro-7-phosphono-7-sulfono-1-pyrindines; ##STR19##referred to herein as octahydro-7-phosphono-7-sulfono-2-pyrindines;

Also preferred are substituted or unsubstituted octahydrophosphonosulfono pyrindiniums having the general structures: ##STR20##referred to herein as octahydro-5-phosphono-5-sulfono-1-pyrindinium;##STR21## referred to herein asoctahydro-5-phosphono-5-sulfono-2-pyrindinium;

(3) ##STR22## referred to herein asoctahydro-6-phosphono-6-sulfono-1-pyrindinium; ##STR23## referred toherein as octahydro-6-phosphono-6-sulfono-2-pyrindinium; ##STR24##referred to herein as octahydro-7-phosphono-7-sulfono-1-pyrindinium; and##STR25## referred to herein asoctahydro-7-phosphono-7-sulfono-2-pyrindinium.

Specific examples of compounds of the present invention are: ##STR26##and the pharmaceutically-acceptable salts and esters thereof.

The term "pharmaceutically-acceptable salts and esters", as used herein,means hydrolyzable esters and salts of the phosphonosulfonate compoundswhich have the same general pharmacological properties as the acid formfrom which they are derived, and which are acceptable from a toxicityviewpoint. Pharmaceutically acceptable salts include alkali metals(e.g., sodium and potassium), alkaline earth metals (e.g., calcium andmagnesium), non-toxic heavy metals (e.g., stanous and indium), andammonium and low molecular weight substituted ammonium (e.g., mono-, di-and triethanolamine) salts. Preferred compounds are the sodium,potassium, and ammonium salts.

In order to determine and assess pharmacological activity, testing ofthe phosphonosulfonate compounds in animals is carried out using variousassays known to those skilled in the art. Thus, the in vivo boneantiresorptive activity may be conveniently demonstrated using an assaydesigned to test the ability of these compounds to inhibit theresorption of bone, which bone resorption is characteristic of abnormalcalcium and phosphate metabolism. One such test known to those skilledin the an is the Schenk model. Another useful art-known test is theadjuvant arthritis test. Also useful is the in vitro hydroxyapatitecrystal growth inhibition test. These and other appropriate tests forpharmacological activity are disclosed and/or referred to in Shinoda etal., Calcified Tissue International, 35, pp 87-99 (1983); Schenk et al.,Calcified Tissue Research, 11, pp 196-214 (1973); Russell et al.,Calcified Tissue Research, 6, pp 183-196 (1970); Muhlbauer and Fleisch,Mineral Electrolyte Metab., 5, pp 296-303 (1981); Nancollas et al., OralBiol., 15, 731 (1970); U.S. Pat. No. 3,683,080, to Francis, issued Aug.8, 1972; U.S. Pat. No. 4,134,969, to Schmidt-Dunker, issued Jan. 16,1979; and EPO Patent Application Publication No. 189,662, published Aug.6, 1986; the disclosures of all these articles and patent specificationsbeing incorporated herein by reference in their entirety. Certain ofthese tests for pharmacological activity are also described in moredetail in the Examples provided hereinafter.

In addition to being useful for treating or preventing pathologicalconditions characterized by abnormal calcium or phosphate metabolism,the compounds of the present invention may have other uses. For example,the compounds of the present invention are believed to be useful as bonescanning agents after labeling with 99m-technetium. In addition, thecompounds of the present invention are useful as sequestering agents forpolyvalent metal ions, particularly di-(e.g. calcium and magnesium) andtrivalent (e.g. indium) metal ions. Thus, the compounds of the presentinvention are useful as builders in detergents and cleansers, or fortreating water. They are also useful as stabilizers for compounds. Inaddition, they may be useful in preventing the formation of tartar(i.e., calculus) and/or plaque on teeth. Finally, the compounds of thepresent invention may be useful as herbicides which are nontoxic toanimals.

The phosphonosulfonate compounds of the present invention are preparedfrom commercially-available materials according to non-limiting Examples1 to 61. Generally, the synthesis reaction may be carried out in thefollowing way: In a first step, a compound containing a carbon geminallysubstituted with a phosphono group and a sulfono group (for examplemethyl 1-dimethoxyphosphinylethenesulfonate ordiethoxyphosphinylmethanesulfonate lithium salt) is coupled with asecond compound to produce a product with a new group off of thegeminally substituted carbon. If so desired, the geminally substitutedcarbon can be hydroxylated in a second step. In a third step, anyphosphonic and sulfonic esters are removed. In a fourth step, ifsaturated heterocyclic tings are desired, hydrogenation is carried out.If quaternary amines are desired, these may be produced in a fifth stepby reaction with alkylating reagents. Finally, if different salts aredesired these may be prepared, for example, by conversion with ionexchange resins in the proper salt form.

Compositions Containing Novel Phosphonosulfonate Compounds

The phosphonosulfonate compounds of the present invention may beadministered to humans or other mammals by a variety of routes,including, but not limited to, oral dosage forms and injections(intravenous, intramuscular, intraperitoneal and subcutaneous). Numerousother dosage forms containing the novel phosphonosulfonate compounds ofthe present invention can be readily formulated by one skilled in theart, utilizing the suitable pharmaceutical excipients as defined below.For considerations of patient compliance, oral dosage forms aregenerally most preferred.

The term "pharmaceutical composition" as used herein means a combinationcomprised of a safe and effective amount of the phosphonosulfonatecompound active ingredient, or mixtures thereof, andpharmaceutically-acceptable excipients.

The phrase "safe and effective amount", as used herein, means an amountof a compound or composition great enough to significantly positivelymodify the symptoms and/or condition to be treated, but small enough toavoid serious side effects (at a reasonable benefit/risk ratio), withinthe scope of sound medical judgment. The safe and effective amount ofactive ingredient for use in the pharmaceutical compositions to be usedin the method of the invention herein will vary with the particularcondition being treated, the age and physical condition of the patientbeing treated, the severity of the condition, the duration of thetreatment, the nature of concurrent therapy, the particular activeingredient being employed, the particular pharmaceutically-acceptableexcipients utilized, and like factors within the knowledge and expertiseof the attending physician.

The term "pharmaceutically-acceptable excipients" as used hereinincludes any physiologically inert, pharmacologically inactive materialknown to one skilled in the art, which is compatible with the physicaland chemical characteristics of the particular phosphonosulfonatecompound active ingredient selected for use. Pharmaceutically-acceptableexcipients include, but are not limited to, polymers, resins,plasticizers, fillers, binders, lubricants, glidants, disintegrants,solvents, co-solvents, buffer systems, surfactants, preservatives,sweetening agents, flavoring agents, pharmaceutical grade dyes orpigments, and viscosity agents.

The term "oral dosage form" as used herein means any pharmaceuticalcomposition intended to be systemically administered to an individual bydelivering said composition to the gastrointestinal tract of anindividual, via the mouth of said individual. For purposes of thepresent invention, the delivered form can be in the form of a tablet,coated or non-coated; solution; suspension; or a capsule, coated ornon-coated.

The term "injection" as used herein means any pharmaceutical compositionintended to be systemically administered to a human or other mammal, viadelivery of a solution or emulsion containing the active ingredient, bypuncturing the skin of said individual, in order to deliver saidsolution or emulsion to the circulatory system of the individual eitherby intravenous, intramuscular, intraperitoneal or subcutaneousinjection.

Compounds of the present invention may comprise from about 0.1% to about99.9% by weight of the pharmaceutical compositions of the presentinvention. Preferably the compounds of the present invention comprisefrom about 20% to about 80% by weight of the pharmaceutical compositionsof the present invention.

Accordingly, the pharmaceutical compositions of the present inventioninclude from 15-95% of a phosphonosulfonate compound active ingredient,or mixture, thereof, 0-2% flavoring agents; 0-50% co-solvents; 0-5%buffer system; 0-2% surfactants; 0-2% preservatives; 0-5% sweeteners;0-5% viscosity agents; 0-75% fillers; 0.5-2% lubricants; 1-5% glidants;4-15% disintegrants; and 1-10% binders.

Suitable pharmaceutical compositions are described here in Examples62-64. It is well within the capabilities of one skilled in the art tovary the non-limiting examples described herein to achieve a broad rangeof pharmaceutical compositions.

The choice of a pharmaceutically-acceptable excipient to be used inconjunction with the phosphonate compounds of the present invention isbasically determined by the way the phosphonate compound is to beadministered. If the compound is to be injected, the preferredpharmaceutical carrier is sterile physiological saline, the pH of whichhas been adjusted to about 7.4. Suitable pharmaceutically-acceptablecarriers for topical application include those suited for use in creams,gels, tapes and the like.

The pharmaceutically-acceptable carrier employed in conjunction with thephosphonosulfonate compounds of the present invention is used at aconcentration sufficient to provide a practical size to dosagerelationship. The pharmaceutically-acceptable carriers, in total, maycomprise from 0.1% to 99.9% by weight of the pharmaceutical compositionsof the present invention, and preferably from 20% to 80%.

The preferred mode of administering the phosphonosulfonate compound ofthe present invention is orally. The preferred unit dosage form istherefore tablets, capsules and the like, comprising a safe andeffective amount of the phosphonate compound of the present invention.Preferably, the compositions comprise from about 1 mg P to about 600 mgP of a phosphonosulfonate compound of the present invention.Pharmaceutically-acceptable carriers suitable for the preparation ofunit dosage forms for oral administration are well known in the art.Their selection will depend on secondary considerations like taste,cost, and shelf stability, which are not critical for the purposes ofthe present invention, and can be made without difficulty by a personskilled in the art.

The term "mg P", as used herein, means the weight of the phosphorus atompresent in an amount of a phosphonosulfonate compound of the presentinvention. This unit is used to standardize the amount of thephosphonosulfonate compounds of the present invention to be used in thepharmaceutical compositions and methods of the present inventions. Forexample, 1-hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic acid has amolecular weight of 283 g/mole, of which 11% (31 g/mole) is due to thephosphorus atom present in this molecule. One milligram of this compoundis therefore calculated to have 0.11 mg P. Thus, to prepare apharmaceutical composition containing 0.11 mg P of this compound, thecomposition should contain 1 mg of the compound; and to dose 0.11 mgP/kg of this compound to a 50 kg patient, the patient would be dosedwith 50 mg of this compound.

The rate of systemic delivery can be satisfactorily controlled by oneskilled in the art, by manipulating any one or more of the following:

(a) the active ingredient;

(b) the pharmaceutically-acceptable excipients; so long as the variantsdo not interfere in the activity of the particular active ingredientselected;

(c) the type of the excipient, and the concomitant desirable thicknessand permeability (swelling properties) of said excipients;

(d) the time-dependent conditions of the excipient itself and/or withinthe excipients;

(e) the particle size of the granulated active ingredient; and

(f) the pH-dependent conditions of the excipients.

In particular, the solubility, acidity, and susceptibility to hydrolysisof the different phosphonosulfonate active ingredients, such as acidaddition salts, salts formed with the carboxylic group, e.g., alkalimetal salts, alkaline earth metal salts, etc., and esters, e.g., alkyl,alkenyl, aryl, aralkyl, may be used as guidelines for the proper choice.In addition, suitable pH-conditions might be established within the oraldosage forms by adding a suitable buffer to the active ingredient inaccordance with the desired release pattern.

As stated hereinabove, pharmaceutically-acceptable excipients include,but are not limited to, resins, fillers, binders, lubricants, solvents,glidants, disintegrants co-solvents, surfactants, preservatives,sweetener agents, flavoring agents, buffer systems, pharmaceutical-gradedyes or pigments, and viscosity agents.

The preferred solvent is water.

Flavoring agents among those useful herein include those described inRemington's Pharmaceutical Sciences, 18th Edition, Mack PublishingCompany, 990, pp. 1288-1300, incorporated by reference herein. Thepharmaceutical compositions suitable for use herein generally containfrom 0-2% flavoring agents.

Dyes or pigments among those useful herein include those described inHandbook of Pharmaceutical Excipients, pp. 81-90, 1986 by the AmericanPharmaceutical Association & the Pharmaceutical Society of GreatBritain, incorporated by reference herein. The pharmaceuticalcompositions herein generally contain from 0-2% dyes or pigments.

Preferred co-solvents include, but are not limited to, ethanol,glycerin, propylene glycol, polyethylene glycols. The pharmaceuticalcompositions of the present invention include from 0-50% co-solvents.

Preferred buffer systems include, but are not limited to, acetic, boric,carbonic, phosphoric, succinic, malaic, tartaric, citric, acetic,benzoic, lactic, glyceric, gluconic, glutaric and glutamic adds andtheir sodium, potassium and ammonium salts. Particularly preferred arephosphoric, tartaric, citric, and acetic acids and salts. Thepharmaceutical composition of the present invention generally containfrom 0-5% buffer systems.

Preferred surfactants include, but are not limited to, polyoxyethylenesorbitan fatty acid esters, polyoxyethylene monoalkyl ethers, sucrosemonoesters and lanolin esters and ethers, alkyl sulfate salts, sodium,potassium, and ammonium salts of fatty acids. The pharmaceuticalcompositions of the present invention include 0-2% surfactants.

Preferred preservatives include, but are not limited to, phenol, alkylesters of parahydroxybenzoic acid, o-phenylphenol benzoic acid and thesalts thereof, boric acid and the salts thereof, sorbic acid and thesalts thereof, chlorobutanol, benzyl alcohol, thimerosal, phenylmercuricacetate and nitrate, nitromersol, benzalkonium chloride, cetylpyridiniumchloride, methyl paraben, and propyl paraben. Particularly preferred arethe salts of benzoic acid, cetylpyridinium chloride, methyl paraben andpropyl paraben. The compositions of the present invention generallyinclude from 0-2% preservatives.

Preferred sweeteners include, but are not limited to, sucrose, glucose,saccharin, sorbitol, mannitol, and aspartame. Particularly preferred aresucrose and saccharin. Pharmaceutical compositions of the presentinvention include 0-5% sweeteners.

Preferred viscosity agents include, but are not limited to,methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium alginate, carbomer,povidone, acacia, guar gum, xanthan gum and tragacanth. Particularlypreferred are methylcellulose, carbomer, xanthan gum, guar gum,povidone, sodium carboxymethylcellulose, and magnesium aluminumsilicate. Compositions of the present invention include 0-5% viscosityagents.

Preferred fillers include, but are not limited to, lactose, mannitol,sorbitol, tribasic calcium phosphate, dibasic calcium phosphate,compressible sugar, starch, calcium sulfate, dextro and microcrystallinecellulose. The compositions of the present invention contain from 0-75%fillers.

Preferred lubricants include, but are not limited to, magnesiumstearate, stearic acid, and talc. The pharmaceutical compositions of thepresent invention include 0.5-2% lubricants.

Preferred glidants include, but are not limited to, talc and colloidalsilicon dioxide. The compositions of the present invention include from1-5% glidants.

Preferred disintegrants include, but are not limited to, starch, sodiumstarch glycolate, crospovidone, croscarmelose sodium, andmicrocrystalline cellulose. The pharmaceutical compositions of thepresent invention include from 4-15% disintegrants.

Preferred binders include, but are not limited to, acacia, tragacanth,hydroxypropylcellulose, pregelatinized starch, gelatin, povidone,hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose,sugar solutions, such as sucrose and sorbitol, and ethylcellulose. Thecompositions of the present invention include 1-10% binders.

Method for Treating or Preventing Diseases Characterized by AbnormalCalcium and Phosphate Metabolism

Another aspect of the present invention is methods for treating orpreventing diseases characterized by abnormal calcium and phosphatemetabolism. Such methods comprise administering to a human or loweranimal in need of such treatment a safe and effective amount of aphosphonosulfonate compound of the present invention.

The preferred mode of administration is oral, but other known methods ofadministration are contemplated as well, e.g., dermato mucosally (forexample, dermally, rectally and the like) and parenterally (for example,by subcutaneous injection, intramuscular injection, intra-articularinjection, intravenous injection and the like). Inhalation is alsoincluded. Thus, specific modes of administration include, withoutlimitation, oral, transdermal, mucosal, sublingual, intramuscular,intravenous, intraperitoneal, and sub cutaneous administration, as wellas topical application.

The term "abnormal calcium and phosphate metabolism", as used herein,means (1) conditions which are characterized by anomalous mobilizationof calcium and phosphate leading to general or specific bone loss, orexcessively high calcium and phosphate levels in the fluids of the body;and (2) conditions which cause or result from deposition of calcium andphosphate anomalously in the body. The first category includes, but isnot limited to, osteoporosis, Paget's disease, hyperparathyroidism,hypercalcemia of malignancy, heterotopic ossification, and osteolyticbone metastases. The second category includes, but is not limited to,myositis ossificans progressiva, calcinosis universalis, and suchafflictions as arthritis, osteoarthritis, neuritis, bursitis, tendonitisand other inflammatory conditions which predispose involved tissue todeposition of calcium phosphates.

The term "rheumatoid arthritis" as used herein, means a chronic systemicand articular inflammatory disorder of unknown etiology. It ischaracterized by destruction of articular cartilage, ligaments, tendons,and bone.

The term "osteoarthritis" as used herein, means a non-inflammatorydisorder of the movable joints. It is characterized by deterioration andabrasion of the articular cartilage; and new bone formation at the jointsurface.

The terms "person at risk" and "person in need of such treatment", asused herein, mean any human or lower animal which suffers a significantrisk of abnormal calcium and phosphate metabolism if left untreated, andany human or lower animal diagnosed as being afflicted with abnormalcalcium and phosphate metabolism. For example, postmenopausal women;persons undergoing certain steroid therapy; persons on certainanticonvulsant drugs; persons diagnosed as having Paget's disease,hyperparathyroidism, hypercalcemia of malignancy, or osteolytic bonemetastases; persons diagnosed as suffering from one or more of thevarious forms of osteoporosis; persons belonging to a population groupknown to have a significantly higher than average chance of developingosteoporosis, e.g., postmenopausal women, men over age 65, and personsbeing treated with drugs known to cause osteopetrosis as a side effect;persons diagnosed as suffering from myositis ossificans progressiva orcalcinosis universalis; and persons afflicted with arthritis,osteoarthritis, neuritis, bursitis, tendonitis and other inflammatoryconditions which predispose involved tissue to deposition of calciumphosphate.

The phrase "safe and effective amount", as used herein, means an amountof a compound or composition high enough to significantly positivelymodify the condition to be treated, but low enough to avoid serious sideeffects (at a reasonable benefit/risk ratio), within the scope of soundmedical judgment. The safe and effective amount of phosphonosulfonatecompounds of the present invention will vary with the particularcondition being treated, the age and physical condition of the patientbeing treated, the severity of the condition, the duration of thetreatment, the nature of concurrent therapy, the specific diphosphonateemployed, the particular pharmaceutically-acceptable carrier utilized,and like factors within the knowledge and expertise of the attendingphysician. However, single dosages can range from 0.01 mg P to 3500 mgP, or from 0.0002 to 70 mg P/kg of body weight (based on a body weightof 50 kg). Preferred single dosages are from 1 mg P to 600 mg P, or from0.02 to 12 mg P/kg of body weight (based on a body weight of 50 kg). Upto four single dosages per day may be administered. Daily dosagesgreater than 500 mg P/kg are not required to produce the desired effectand may produce undesirable side effects. The higher dosages within thisrange are, of course, required in the case of oral administrationbecause of limited absorption.

The following Examples further describe and demonstrate the preferredembodiments within the scope of the present invention. The Examples aregiven solely for the purpose of illustration, and are not to beconstrued as limitations of the present invention since many variationsthereof are possible without departing from its spirit and scope.

EXAMPLE 1

Synthesis of 2-(1-Imidazolyl)-1-phosphonoethanesulfonic Acid ##STR27##

A mixture of 0.68 g (0.01 mole) of imidazole and 2.30 g (0.01 mole) ofmethyl 1-dimethoxyphosphinylethenesulfonate (U.S. Pat. No. 5,011,938issued to Barnett et al. on Apr. 30, 1991) in 20 ml of chloroform isstirred at 20°-50° for one day. The reaction is cooled to roomtemperature, and 10.7 g (0.07 mole) of bromotrimethylsilane is added.The mixture is stirred at 20°-30° for 2-3 days, and to it is then added20 ml water. The mixture is stirred for about 30 minutes, and the layersare separated. The water layer is extracted several times with CHCl₃(extracts are discarded) and is evaporated to dryness under vacuum. Theresidue is triturated with acetone to give a solid, which is collectedby filtration and recrystallized from water/acetone to afford2-(1-imidazolyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 2

Synthesis of 1-Phosphono-2-(3-pyridylamino)ethanesulfonic Acid ##STR28##

This compound is synthesized in the manner of Example 1, starting with3-aminopyridine.

EXAMPLE 3

Synthesis of 1-Phosphono-2-(3-piperidinylamino)ethanesulfonic Acid##STR29##

A mixture of 1 g of 1-phosphono-2-(3-pyridinylamino)ethanesulfonic acidand 0.5 g of palladium on charcoal catalyst in 50 ml of distilled wateris hydrogenated on a Parr apparatus at 40 PSI for about 2 days. Thecatalyst is removed by filtration, and the filtrate is concentrated to afew mls. Ethanol is added slowly to precipitate a solid, which isrecrystallized from water/ethanol to afford1-phosphono-2-(3-piperidinylamino)ethanesulfonic acid.

EXAMPLE 4

Synthesis of 1-Phosphono-2-(2-pyridinylamino)ethanesulfonic Acid##STR30##

This compound is synthesized in the manner of Example 1, starting with2-aminopyridine.

EXAMPLE 5

Synthesis of 1-Phosphono-2-((2-piperidinylidene)amino)ethanesulfonicAcid ##STR31##

This compound is synthesized by the procedure of Example 3, startingwith 1-phosphono-2-(2-pyridinylamino)ethanesulfonic acid.

EXAMPLE 6

Synthesis of 1-Phosphono-2-(2-pyrimidinylamino)ethanesulfonic Acid##STR32##

This compound is synthesized in the manner of Example 1, starting with2-aminopyrimidine.

EXAMPLE 7

Synthesis of 1-Phosphono-2-((1,3-diazacyclohexane-2-ylidene)amino)ethanesulfonic Acid ##STR33##

This compound is synthesized by the procedure of Example 3, startingwith 1-phosphono-2-(2-pyrimidinylamino)ethanesulfonic acid.

EXAMPLE 8

Synthesis of 1-Phosphono-2-(N-methyl(2-pyridinyl)amino)ethanesulfonicAcid ##STR34##

This compound is synthesized in the manner of Example 1, starting with2-methylaminopyridine.

EXAMPLE 9

Synthesis of 2-(N-methyl)(3,4,5,6-tetrahydropyridin-2-yl)amino!-1-phosphonoethanesulfonicAcid ##STR35##

This compound is synthesized by the procedure of Example 3, startingwith 2- N-methyl(2-pyridinyl)amino!-1-phosphonoethanesulfonic acid.

EXAMPLE 10

Synthesis of 1-Phosphono-2-(1-pyrrolidinyl)ethanesulfonic Acid ##STR36##

This compound is synthesized by the method of Example 1, starting withpyrrolidine.

EXAMPLE 11

Synthesis of 2-Hexahydro-1H-azepin-1-yl)-1-(phosphono)ethanesulfonicAcid ##STR37##

This compound is synthesized by the method of Example 1, starting withhexamethyleneimine.

EXAMPLE 12

Synthesis of 2-(Cyclohexylamino)-1-phosphonoethanesulfonic Acid##STR38##

This compound is synthesized by the method of Example 1, starting withcyclohexylamine.

EXAMPLE 13

Synthesis of 2- 2-(Dimethylamino)ethylamino!-1-phosphonoethanesulfonicAcid ##STR39##

This compound is synthesized by the method of Example 1, starting withN,N-dimethylethylenediamine.

EXAMPLE 14

Synthesis of2- 2-(Dimethylamino)ethylthio!-1-phosphonoethanesulfonicAcid ##STR40##

This compound is synthesized by the method of Example 1, starting with2-dimethylaminoethanethiol.

EXAMPLE 15

Synthesis of 3-Amino-1-phosphonopropanesulfonic Acid ##STR41## I.Synthesis of Methyl 2-Cyano-1-(dimethoxyphosphinyl)ethanesulfonate

To a solution of 2.3 g (0.01 mole) of methyl1-dimethoxyphosphinylethylenesulfonate in a mixture of 20 ml ethanol and10 ml water is added 0.60 g (0.01 mole) of acetic acid followed by 1.3 g(0.02 mole) of potassium cyanide. The mixture is stirred at roomtemperature for 1-5 hours, 20 ml more water is added, and the mixture isconcentrated under vacuum on a rotary evaporator to get rid of theethanol. The reaction is extracted several times with chloroform. Thecombined extracts are dried (MgSO₄) and the solvent is removed. Theresulting oily residue is purified by flash chromatography on silicagel.

II. Synthesis of 2-Cyano-1-phosphonoethanesulfonate

A solution of 2.57 g (0.01 mole) of methyl2-cyano-1-(dimethoxyphosphinyl)ethanesulfonate in 30 ml chloroform istreated with 10.7 g (0.07 mole) of bromotrimethylsilane. The solution isstirred at room temperature for 2-3 days. Water (20 ml) is added, andthe mixture is vigorously stirred for 30 minutes. The solvents areremoved under vacuum on a rotary evaporator, and the residue istriturated with acetone to afford 2-cyano-1-phosphonoethanesulfonate.

III. Synthesis of 3-Amino-1-phosphonopropanesulfonic Acid

The hydrogenation of 2-cyano-1-phosphonoethanesulfonate is carried outusing the hydrogenation technique of Freifelder (J. Am. Chem. Soc., 82,2386 (1960)). The cyano compound (2.15 g; 0.01 mole) is placed in 20 mlof 10% methanolic ammonia. Rhodium on alumina (5%) catalyst (0.5 g) isadded, and the mixture is hydrogenated at 40 PSI on a Parr apparatus forseveral hours (until uptake of hydrogen is complete). The catalyst isfiltered off, and the filtrate is evaporated dry. The product ispurified by dissolving the residue in water, adding ethanol to give aprecipitate, and collecting the solids by filtration. Furtherpurification is accomplished by again recrystallizing fromwater/ethanol.

EXAMPLE 16

Synthesis of 1-Phosphono-2-(3-pyridyl)ethanesulfonic Acid ##STR42## I.Synthesis of 1-Diethoxyphosphinyl-2-(3-pyridyl)ethanesulfonic AcidLithium Salt

A suspension of 2.38 g (0.1 mole) of diethoxyphosphinylmethanesulfonatelithium salt (Carretero, et al.; Tetrahedron,. 43, 5125 (1987)) in 50 mlof anhydrous tetrahydrofuran is stirred in a -40° bath under a drynitrogen atmosphere. To this is added n-butyl lithium (4.4 ml of 2.5Msolution in hexanes; 0.011 mole) via syringe over 5 minutes. Thereaction mixture is allowed to warm to -15°, and is stirred at thistemperature for about one hour. It is then cooled to -78°, and to it isadded dropwise over about 5 minutes a solution of 1.27 g (0.1 mole) of3-(chloromethyl)pyridine in 3 ml of anhydrous THF.(3-(chloromethyl)pyridine is prepared by dissolving a few grams of3-picolylchloride hydrochloride in a minimum quantity of water andcarefully adding excess solid K₂ CO₃ until foaming stops and the waterhas been absorbed by the K₂ CO₃ leaving the 3-picolylchloride floatingon the surface as an oil. This is extracted with a few ml of methylenechloride. The solution is dried with MgSO₄ and is evaporated to drynessunder vacuum to give 3-(chloromethyl)pyridine. This must be preparedfresh for each use, and heat should be avoided to minimizedecomposition. (3-(chloromethyl)pyridine is a severe irritant, and caremust be taken in handling it.) The reaction mixture is stirred for 1hour at -78°, and is then allowed to warm to room temperature overseveral hours as the bath warms up. It is stirred at ambient temperaturefor several hours, and is then quenched by addition of 1.2 g (0.02 mole)of acetic acid. The reaction mixture is evaporated to dryness on arotary evaporator, and the resulting residue is purified by flashchromatography on silica gel using chloroform/methanol as eluant to give1-diethoxyphosphinyl-2-(3-pyridyl)ethanesulfonic acid lithium salt.

II. Synthesis of 1-Phosphono-2-(3-pyridyl)ethanesulfonic Acid

The above diester is hydrolyzed by dissolving it (2 g) in 20 ml of 6NHCl and heating this solution at reflux for 12-24 hours. It is thenevaporated to dryness under vacuum. The residue is dissolved in waterand is treated with cation exchange resin in H⁺ form to remove Li salts.The solution is taken to dryness on a rotary evaporator, and the residueis triturated with acetone. The resulting solid is filtered off andrecrystallized from water/ethanol to field1-phosphono-2-(3-pyridyl)ethanesulfonic acid.

EXAMPLE 17

Synthesis of 1-Methyl-3-(2-phosphono-2-sulfonoethyl)pyridinium Iodide##STR43##

A solution of 2.67 g (0.01 mole) of1-phosphono-2-(3-pyridinyl)ethanesulfonic acid (prepared as described inExample 16) in 20 ml water and 30 ml ethanol is adjusted to pH 7.0 byaddition of 1N aqueous NaOH. To this is added 7.1 g (0.05 mole) ofmethyl iodide, and the reaction is stirred at 30°-50° for one day. Thereaction is evaporated to dryness under reduced pressure. The resultingresidue is dissolved in distilled water, and is treated with cationexchange resin in H⁺ form. The resin is filtered off and the aqueoussolution is evaporated to dryness under vacuum. The residue istriturated with acetone to give a solid which is collected byfiltration. This is purified by recrystallization from water/acetone togive N-methyl-3-(2-phosphono-2-sulfonoethyl)pyridinium iodide.

EXAMPLE 18

Synthesis of N-Ethyl-3-(2-phosphono-2-sulfonoethyl)pyridinium Iodide##STR44##

A solution of 2.67 g (0.01 mole) of1-phosphono-2-(3-pyridyl)ethanesulfonic acid (prepared as described inExample 16) in 20 ml water and 40 ml ethanol is adjusted to pH 7.0 byaddition of 1N aqueous NaOH. To this is added 6.24 g (0.04 mole) ofethyl iodide, and the reaction is stirred at 30°-50° for one day. Thereaction is evaporated to dryness under reduced pressure. The resultingresidue is dissolved in distilled water, and is treated with cationexchange resin in H⁺ form. The resin is filtered off, the aqueoussolution is concentrated to a few ml, and acetone is added dropwise toprecipitate the product. This is purified by recrystallization fromwater/acetone to give N-ethyl-3-(2-phosphono-2-sulfonoethyl)pyridiniumiodide.

EXAMPLE 19

Synthesis ofN-(2-(Acetylthio)ethyl)-3-(2-phosphono-2-sulfonoethyl)pyridinium Bromide##STR45##

A solution of 2.67 g (0.01 mole) of1-phosphono-2-(3-pyridyl)ethanesulfonic acid (prepared as described inExample 16) in 20 ml water and 40 ml ethanol is adjusted to pH 7.0 byaddition of 1N aqueous NaOH. To this is added 9.16 g (0.05 mole) ofS-acetyl-2-bromoethanethiol, and the reaction is heated at 40°-80° forseveral hours. The reaction is evaporated to dryness under reducedpressure. The resulting residue is triturated with acetone several times(acetone extracts are discarded). The remaining solid is dissolved indistilled water, and is treated with cation exchange resin in H⁺ form.The resin is filtered off, the aqueous solution is concentrated to a fewml, and acetone is added dropwise to precipitate the product. This ispurified by recrystallization from water/acetone to giveN-(2-(acetylthio)ethyl)-3-(2-phosphono-2-sulfonoethyl)pyridiniumbromide.

EXAMPLE 20

Synthesis of 3-(2-Phosphono-2-sulfonoethyl)-N-(2-thioethyl)pyridiniumChloride ##STR46##

A solution of 1 g ofN-(2-(acetylthio)ethyl)-3-(2-phosphono-2-sulfonoethyl)pyridinium bromidein 50 ml of water is treated with anion exchange resin in chloride form.The solution is concentrated to 20 ml, and 20 ml of 12N HCl is added.The solution is heated at reflux under a nitrogen atmosphere for 12hours, and is then evaporated dry. The residue is dissolved in 50 ml offresh 6N HCl and is again evaporated to dryness. It is then taken up ina few ml of water and is reprecipitated with ethanol to yield3-(2-phosphono-2-sulfonoethyl)-N-(2-thioethyl)pyridinium chloride. Allof these operations are carried out under N₂ atmosphere usingdeoxygenated solvents to minimize disulfide formation.

EXAMPLE 21

Synthesis of 1-Phosphono-2-(2-pyridyl)ethanesulfonic Acid ##STR47##

This compound is synthesized according to the method in Example 16,starting with 2-picolyl chloride hydrochloride.

EXAMPLE 22

Synthesis of N-Methyl-2-(2-phosphono-2-sulfonoethyl)pyridinium Iodide##STR48##

This compound is synthesized by the method of Example 17, starting with1-phosphono-2-(2-pyridyl)ethanesulfonic acid.

EXAMPLE 23

Synthesis of N-Ethyl-2-(2-phosphono-2-sulfonoethyl)pyridinium Iodide##STR49##

This compound is synthesized by the method of Example 18, starting with1-phosphono-2-(2-pyridyl)ethanesulfonic acid.

EXAMPLE 24

Synthesis ofN-(2-(Acetylthio)ethyl)-2-(2-phosphono-2-sulfonoethyl)pyridinium Bromide##STR50##

This compound is synthesized by the method of Example 19 starting with1-phosphono-2-(2-pyridyl)ethanesulfonic acid.

EXAMPLE 25

Synthesis of 2-(2-Phosphono-2-sulfonoethyl)-N-(2-thioethyl)pyridiniumChloride ##STR51##

This compound is synthesized by the method of Example 20 starting withN-(2-(acetylthio)ethyl)-2-(2-phosphono-2-sulfonoethyl)pyridiniumbromide.

EXAMPLE 26

Synthesis of 2-(1-Methyl-2-piperidinyl)-1-phosphonoethanesulfonic Acid##STR52##

A mixture of 1 g of N-methyl-2-(2-phosphono-2-sulfonoethyl)pyridiniumiodide and 0.5 g of palladium on charcoal catalyst in 50 ml of distilledwater is hydrogenated on a Parr apparatus at 40 PSI for about 2 days.The catalyst is removed by filtration, and the filtrate is concentratedto a few mls. Ethanol is added slowly to precipitate a solid, which isrecrystallized from water/ethanol to afford2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 27

Synthesis of N,N-Dimethyl-2-(2-phosphono-2-sulfonoethyl)piperidiniumIodide ##STR53##

This is prepared by the method used in Example 17, starting with2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 28

Synthesis of N-Methyl-N-ethyl-2-(2-phosphono-2-sulfonoethyl)piperidiniumIodide ##STR54##

This is prepared by the method used in Example 18, starting with2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 29

Synthesis ofN-(2-(Acetylthio)ethyl)-N-methyl-2-(2-phosphono-2-sulfonoethyl)piperidiniumBromide ##STR55##

This is prepared by the method used in Example 19, starting with2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 30

Synthesis ofN-Methyl-N-(2-thioethyl)-2-(2-phosphono-2-sulfonoethyl)piperidiniumChloride ##STR56##

This is prepared by the method used in Example 20, starting withN-(2-(acetylthio)ethyl)-N-methyl-2-(2-phosphono-2-sulfonoethyl)piperidiniumbromide.

EXAMPLE 31

Synthesis of 2-(2-Piperidinyl)-1-phosphonoethanesulfonic Acid ##STR57##

A mixture of 1 g of 1-phosphono-2-(2-pyridinyl)ethanesulfonic acid and0.5 g of palladium on charcoal catalyst in 50 ml of distilled water ishydrogenated on a Parr apparatus at 40 PSI for about 2 days. Thecatalyst is removed by filtration, and the filtrate is concentrated to afew mls. Ethanol is added slowly to precipitate a solid, which isrecrystallized from water/ethanol to afford1-phosphono-2-(2-piperidinyl)ethanesulfonic acid.

EXAMPLE 32

Synthesis of 2-(3-Piperidinyl)-1-phosphonoethanesulfonic Acid ##STR58##

This compound is prepared by the method of Example 31 starting with1-phosphono-2-(3-pyridinyl)ethanesulfonic acid.

EXAMPLE 33

Synthesis of 2-(1-Methyl-3-piperidinyl)-1-phosphonoethanesulfonic Acid##STR59##

This compound is prepared by the method of Example 26, starting with1-methyl-3-(2-phosphono-2-sulfonoethyl)pyridinium iodide.

EXAMPLE 34

Synthesis of N,N-Dimethyl-3-(2-phosphono-2-sulfonoethyl)piperidiniumIodide ##STR60##

This is prepared by the method used in Example 17, starting with2-(1-methyl-3-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 35

Synthesis ofN-(2-(Acetylthio)ethyl)-N-methyl-3-(2-phosphono-2-sulfonoethyl)piperidiniumBromide ##STR61##

This is prepared by the method used in Example 19, starting with2-(1-methyl-3-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 36

Synthesis ofN-Methyl-N-(2-thioethyl)-3-(2-phosphono-2-sulfonoethyl)piperidiniumChloride ##STR62##

This is prepared by the method used in Example 20, starting withN-(2-(acetylthio)ethyl)-N-methyl-3-(2-phosphono-2-sulfonoethyl)piperidiniumbromide.

EXAMPLE 37

Synthesis of Phosphono(2-pyridinylthio)methanesulfonic acid ##STR63##

A suspension of 2.38 g (0.01 mole) of diethoxyphosphinylmethanesulfonatelithium salt (Carretero, et al.; Tetrahedron, 43, 5125 (1987)) in 50 mlof anhydrous tetrahydrofuran is stirred in a -40° bath under a drynitrogen atmosphere. To this is added n-butyl lithium (4.4 ml of 2.5Msolution in hexanes; 0.011 mole) via syringe over 5 minutes. Thereaction mixture is allowed to warm to -15°, and is stirred at thistemperature for about one hour. To it is then added rapidly a solutionof 2.2 g (0.01 mole) of 2,2'-dipyridyl disulfide in 30 ml of anhydrousTHF. The reaction mixture is stirred for 1 hour at -15°, and is thenallowed to warm to room temperature over several hours as the bath warmsup. It is stirred at ambient temperature for several hours, and is thenquenched by addition of 50 ml of water. The reaction mixture isconcentrated under vacuum on a rotary evaporator to get rid of the THF,and the aqueous layer is extracted with ether to remove some impurities.The water layer is concentrated to 10 ml on a rotary evaporator, and 10ml of 12N HCl is added. The solution is heated at reflux for 12-24hours, and is evaporated to dryness under vacuum. The residue isdissolved in water and is treated with cation exchange resin in H⁺ formto remove Li salts. The solution is taken to dryness on a rotaryevaporator, and the residue is triturated with acetone. The resultingsolid is filtered off and recrystallized from water/ethanol to yieldphosphono(2-pyridinylthio)methanesulfonic acid.

EXAMPLE 38

Synthesis of4-Amino-1-phosphonobutanesulfonic Acid ##STR64## I.Synthesis of 3-Cyano-1-diethoxyphosphinylpropanesulfonic Acid LithiumSalt

A suspension of 2.38 g (0.01 mole) of diethoxyphosphinylmethanesulfonatelithium salt (Carretero, et al.; Tetrahedron, 43, 5125 (1987)) in 50 mlof anhydrous tetrahydrofuran is stirred in a -40° bath under a drynitrogen atmosphere. To this is added n-butyl lithium (4.4 ml of 2.5Msolution in hexanes; 0.011 mole) via syringe over 5 minutes. Thereaction mixture is allowed to warm to -15° and is stirred at thistemperature for about one hour. To it is then added rapidly a solutionof 0.53 g (0.01 mole) of acrylonitrile in 3 ml of anhydrous THF. Thereaction mixture is stirred for 1 hour at -15° , and is then allowed towarm to room temperature over several hours as the bath warms up. It isstirred at ambient temperature for several hours, and then is quenchedby addition of 50 ml of water containing 0.6 g (0.01 mole) of aceticacid. The reaction mixture is concentrated under vacuum on a rotaryevaporator to get rid of the THF, and the aqueous layer is extractedwith ether to remove some impurities. The water layer is evaporated todryness under vacuum, and the resulting residue is purified by flashchromatography on silica gel using chloroform/methanol as eluant, toafford 3-cyano-1-diethoxyphosphinylpropanesulfonic acid lithium salt.

II. Synthesis of 4-Amino-1-phosphonobutanesulfonic Acid

The hydrogenation of 3-cyano-1-diethoxyphosphinylpropanesulfonic acidlithium salt is carried out using the hydrogenation technique ofFreifelder (J. Am. Chem. Soc., 82, 2386 (1960)). The cyano compound(2.62 g; 0.01 mole) is placed in 20 ml of 10% methanolic ammonia.Rhodium on alumina (5%) catalyst (0.5 g) is added, and the mixture ishydrogenated at 40 PSI on a Parr apparatus for several hours (untiluptake of hydrogen is complete). The catalyst is filtered off, and thefiltrate is evaporated dry. The product is hydrolyzed by dissolving theresidue in 25 ml of 6N HCl and refluxing the solution for 12-24 hours.It is then evaporated to dryness under vacuum on a rotary evaporator.Distilled water (25 ml) is added, and the solution is again evaporateddry. The resulting residue is dissolved in a few ml H₂ O, and ethanol isadded to precipitate a solid. This is recrystallized from water/ethanolto yield 4-amino-1-phosphonobutanesulfonic acid.

EXAMPLE 39

Synthesis of 1-Hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic Acid##STR65## I. Synthesis of1-Diethoxyphosphinyl-1-hydroxy-2-(3-pyridinyl)ethanesulfonic AcidLithium Salt

A suspension of 3.29 g (0.01 mole) of1-diethoxyphosphinyl-2-(3-pyridinyl)ethanesulfonic acid lithium salt(from part I of Example 16) in 50 ml of anhydrous tetrahydrofuran isstirred in a -40° bath under a dry nitrogen atmosphere. To this is addedn-butyl lithium (4.4 ml of 2.5M solution in hexanes; 0.011 mole) viasyringe over 5 minutes. The reaction mixture is allowed to warm to -15°, and is stirred at this temperature for about one hour. It is thencooled to -78°, and to it is added dropwise a solution of 3.44 g (0.015mole) of camphorylsulfonyloxaziridine (J. Am. Chem. Soc., 112,6679(1990)) in 50 ml of anhydrous THF. The reaction mixture is stirredfor a few minutes at -78°, and then is placed in an ice/water bath. Itis stirred at 0° for 2-10 minutes, and then is again cooled to -78° .The reaction mixture is quenched by addition of 1.2 g (0.02 mole) ofacetic acid and the solvents are removed under vacuum on a rotaryevaporator. The residue was purified by chromatography on silica gelusing chloroform/methanol as eluant, to yield1-diethoxyphosphinyl-1-hydroxy-2-(3-pyridinyl)ethanesulfonic acidlithium salt.

II. Synthesis of 1-Hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonicAcid

Hydrolysis of the above diester is effected by dissolving it (1 g) in 15ml of 6N HCl and heating the solution at reflux for 12-24 hours. Thesolution is then evaporated to dryness. The residue is redissolved inwater and treated with cation exchange resin in H+ form. The solution isagain taken to dryness and is triturated with acetone to give a solid.This is recrystallized from water/ethanol to yield1-hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic acid.

EXAMPLE 40

Synthesis of 1-Methyl-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumIodide ##STR66##

This compound is synthesized by the method of Example 17, starting with1-hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic acid.

EXAMPLE 41

Synthesis of N-Ethyl-3(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumIodide ##STR67##

This compound is synthesized by the method of Example 18, starting with1-hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic acid.

EXAMPLE 42

Synthesis ofN-(2-(Acetylthio)ethyl)-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumBromide ##STR68##

This compound is synthesized by the method of Example 19, starting with1-hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic acid.

EXAMPLE 43

Synthesis of3-(2-Hydroxy-2-phosphono-2-sulfonoethyl)-N-(2-thioethyl)pyridiniumChloride ##STR69##

This compound is synthesized by the method of Example 20, starting withN-(2-(acetylthio)ethyl)-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumbromide.

EXAMPLE 44

Synthesis of 1-Hydroxy-1-phosphono-2-(2-pyridyl)ethanesulfonic Acid##STR70##

This compound is synthesized according to the method in Example 39,starting with 1-diethoxyphosphinyl-2-(2-pyridinyl)ethanesulfonic acidlithium salt.

EXAMPLE 45

Synthesis of N-Methyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumIodide ##STR71##

This compound is synthesized by the method of Example 17, starting with1-hydroxy-1-phosphono-2-(2-pyridinyl)ethanesulfonic acid.

EXAMPLE 46

Synthesis of N-Ethyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumIodide ##STR72##

This compound is synthesized by the method of Example 18, starting with1-hydroxy-1-phosphono-2-(2-pyridinyl)ethanesulfonic acid.

EXAMPLE 47

Synthesis ofN-(2-(Acetylthio)ethyl)-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumBromide ##STR73##

This compound is synthesized by the method of Example 19 starting with1-hydroxy-1-phosphono-2-(2-pyridinyl)ethanesulfonic acid.

EXAMPLE 48

Synthesis of2-(2-Hydroxy-2-phosphono-2-sulfonoethyl)-N-(2-thioethyl)pyridiniumChloride ##STR74##

This compound is synthesized by the method of Example 20 starting withN-(2-(acetylthio)ethyl)-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridiniumbromide.

EXAMPLE 49

Synthesis of1-Hydroxy-2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic Acid##STR75##

A mixture of 1 g ofN-methyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridinium iodide and0.5 g of palladium on charcoal catalyst in 50 ml of distilled water ishydrogenated on a Parr apparatus at 40 PSI for about 2 days. Thecatalyst is removed by filtration, and the filtrate is concentrated to afew mls. Ethanol is added slowly to precipitate a solid, which isrecrystallized from water/ethanol to afford1-hydroxy-2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 50

Synthesis ofN,N-Dimethyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidinium Iodide##STR76##

This is prepared by the method used in Example 17, starting with1-hydroxy-2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 51

Synthesis ofN-Methyl-N-ethyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumIodide ##STR77##

This is prepared by the method used in Example 18, starting with1-hydroxy-2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 52

Synthesis ofN-(2-(Acetylthio)ethyl)-N-methyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumBromide ##STR78##

This is prepared by the method used in Example 19, starting with1-hydroxy-2-(1-methyl-2-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 53

Synthesis ofN-Methyl-N-(2-thioethyl)-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumChloride ##STR79##

This is prepared by the method used in Example 20, starting withN-(2-(acetylthio)ethyl)-N-methyl-2-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumbromide.

EXAMPLE 54

Synthesis of 1-Hydroxy-2-(2-Piperidinyl)-1-phosphonoethanesulfonic Acid##STR80##

A mixture of 1 g of 1-hydroxy-1-phosphono-2-(2-pyridinyl)ethanesulfonicacid and 0.5 g of palladium on charcoal catalyst in 50 ml of distilledwater is hydrogenated on a Parr apparatus at 40 PSI for about 2 days.The catalyst is removed by filtration, and the filtrate is concentratedto a few mls. Ethanol is added slowly to precipitate a solid, which isrecrystallized from water/ethanol to afford1-hydroxy-1-phosphono-2-(3-piperidinyl)ethanesulfonic acid.

EXAMPLE 55

Synthesis of 1-Hydroxy-2-(3-piperidinyl)-1-phosphonoethanesulfonic Acid##STR81##

This compound is prepared by the method of Example 54 starting with1-hydroxy-1-phosphono-2-(3-pyridinyl)ethanesulfonic acid.

EXAMPLE 56

Synthesis of1-Hydroxy-2-(1-methyl-3-piperidinyl)-1-phosphonoethanesulfonic Acid##STR82##

This compound is prepared by the method of Example 54, starting with1-methyl-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)pyridinium iodide.

EXAMPLE 57

Synthesis ofN,N-Dimethyl-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidinium Iodide##STR83##

This is prepared by the method used in Example 17, starting with1-hydroxy-2-(1-methyl-3-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 58

Synthesis ofN-(2-(Acetylthio)ethyl)-N-methyl-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumBromide ##STR84##

This is prepared by the method used in Example 19, starting with1-hydroxy-2-(1-methyl-3-piperidinyl)-1-phosphonoethanesulfonic acid.

EXAMPLE 59

Synthesis ofN-Methyl-N-(2-thioethyl)-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumChloride ##STR85##

This is prepared by the method used in Example 20, starting withN-(2-(acetylthio)ethyl)-N-methyl-3-(2-hydroxy-2-phosphono-2-sulfonoethyl)piperidiniumbromide.

EXAMPLE 60

Synthesis of Dihydro-6-phosphono-1-pyrindine-6-sulfonic Acid ##STR86##

To 70 ml of anhydrous dimethylsulfoxide (DMSO), stirred under nitrogenatmosphere in an ice bath, is added 1.6 g of 60% NaH in mineral oil(0.04 mole). When this is dissolved, there is added dropwise to thesolution (still stirred at 0°) a solution ofdiethoxyphosphinyl-methanesulfonic acid lithium salt (4.76 g, 0.02 mole)in 30 ml of DMSO. The reaction mixture is stirred at room temperaturefor one hour. To it is then added dropwise a solution of 3.48 g (0.02mole) of 2,3-bis(chloromethyl)pyridine (see K. Tsuda, et al., Chem.Pharm. Bull., 1, 142 (1953)) in 15 mi of DMSO. The mixture is stirred atroom at 80° for 1-3 hours. The DMSO is removed under vacuum, and theresidue is purified by flash chromatography on silica gel using 1-15%methanol in methylene chloride gradient as eluant.

The above ester is hydrolyzed by refluxing it in 6N HCl for 20 hours.Upon concentration of the reaction solution and cooling it in ice aprecipitate forms. This is recrystallized from water to afforddihydro-1-pyrindine-6-phosphono-6-sulfonic acid.

EXAMPLE 61

Synthesis of Octahydro-6-phosphono-1-pyrindine-6-carboxylic Acid##STR87##

1.0 g of dihydro-6-phosphono-1-pyrindine-6-carboxylic acid hydrochloride(from example 60) in 50 ml of H₂ O with 0.5 g of PtO₂ is hydrogenated ona Parr apparatus at 40 PSI for 3 days. The catalyst is filtered off, andthe filtrate is taken to dryness under vacuum. The resulting solid istaken up in the minimum amount of water, and precipitated by slowaddition of ethanol to give octahydro-6-phosphono-1-pyrindine-6-sulfonicacid.

EXAMPLE 62

Capsules are prepared having the following composition:

    ______________________________________                                        Active Ingredient  Mg Per Capsule                                             ______________________________________                                        1-hydroxy-1-phosphono-2-                                                                         350.0                                                      (3-pyridinyl)ethanesulfonic Acid                                              Excipients                                                                    Lactose             90.0                                                      Microcrystalline Cellulose                                                                        60.0                                                      Magnesium Stearate  1.0                                                       ______________________________________                                    

The capsules having the above composition are prepared usingconventional methods as described below:

The active ingredient is mixed with the microcrystalline cellulose in aturn shell blender for approximately ten (10) minutes.

The resulting mixture is passed through a hammer mill with an 80 meshscreen.

The mixture is put back into the twin shell blender along with thelactose and is then mixed for approximately fifteen (15) minutes.

The magnesium stearate is next added and blended for an additional five(5) minutes. The resulting blend is then compressed on apiston-activated capsule filler.

Any of the compounds prepared according to Examples 1 to 61 may besubstituted for the active ingredient in the capsule preparedhereinabove.

EXAMPLE 63

Tablets are prepared having the following composition:

    ______________________________________                                        Active Ingredient        Mg Per Tablet                                        ______________________________________                                        3-(2-Hydroxy-2-phosphono-2-                                                                             700.00                                              sulfonoethyl)-N-(2-thioethyl)pyridinium chloride                              Excipients                                                                    Lactose (spray-dried)    200.0                                                Starch (1500)            100.0                                                Magnesium Stearate        25.0                                                ______________________________________                                    

Tablets are prepared having the above composition using conventionalmethods as described below:

The active ingredient is ground in a ball mill for approximately thirty(30) minutes. The milled active ingredient is then blended in atwinblade mixer with the spray-dried lactose for approximately twenty(20) minutes.

The starch is added to the mixture and is then mixed for an additionalfifteen (15) minutes. The blend is compressed into tablets on a standardtablet press.

Any of the compounds prepared according to Examples 1 to 61 may besubstituted for the active ingredient in the tablet preparedhereinabove.

EXAMPLE 64

Injectable solutions are prepared by conventional methods using 100 mlof physiological saline solution and 70 mg P of3-(2-hydroxy-2-phosphono-2-sulfonoethyl)-N-(2-thioethyl)pyridiniumchloride, adjusted to pH=7.4.

One injection, one time daily for 4 days, results in appreciablealleviation of hypercalcemia of malignancy in patients weighingapproximately 70 kilograms.

Any of the compounds prepared according to Examples 1 to 61 may besubstituted for the active ingredient in the injection preparedhereinabove.

EXAMPLE 65

A Caucasian male, weighing approximately 92 kilograms, seventy-two yearsof age, suffering from moderate to severe pain, and occasional swelling,of the right knee. After approximately one year of steadily increasingdiscomfort, he visits a physician who renders a clinical diagnosis ofosteoarthritis of the right knee, which is subsequently verified byX-ray diagnosis.

After a period of ameliorative therapy of various NSAIDs, includingaspirin, naprosen, and ketoprofen, his symptoms continue to worsen andhis condition appears to degenerate. He returns to his physician whothen prescribes the tablets prepared as described in Example 63 twicedaily two hours before or after meals for a period of three months. Hisclinical symptoms of pain and swelling, particularly with extendedwalking, improves significantly after his 3 months of therapy. At theconfusion of three months at a dosage of 2 tablets per day, the therapyis continued at one-half the dosage originally prescribed (i.e. 1tablets per day) indefinitely.

EXAMPLE 66

A black female, weighing approximately 65 kilograms, fifty-five years ofage, presents with swelling and deformation of the finger joints of bothhands, with partial loss of strength and/or dexterity of her fingers andhands. Upon visual and X-ray examination and various appropriateclinical tests approved by the American Rheumatological Association(ARA) she is diagnosed with rheumatoid arthritis.

After an unsuccessful analgesic and anti-inflammatory therapy, herphysician prescribes the tablets prepared in Example 63, two times dailytwo hours before or after meals for a period of four months. After amonth of therapy, her symptoms of knuckle swelling noticeably improvesand her range of finger motion increases significantly; she continuestherapy for the remainder of the four months, after which her physiciancontinues the prescribed dose for an additional two months.

EXAMPLE 67

A female of Hispanic origin, twelve years of age, weighing approximately37 kilograms, presents to the physician with idiopathic juvenilerheumatoid arthritis. Her symptoms include marked intimation of multiplejoints, complicated by heat and tenderness and indicating rapid andpathological degeneration of joint function.

Her physician refers her to a rheumatologist who immediately prescribesaggressive therapy by IV administration of the solution prepared asdescribed in Example 64 over a period of three days, at the rate of 1injection per day, administered over two hours. At the conclusion of theIV regimen, the physician prescribes the tablets prepared as describedin Example 63, for a period of two months, during which she exhibitsmarked improvement with increased mobility and decreased pain. For thesucceeding two months, the physician reduces her dose to 3/4 of theoriginal oral dose by prescribing 3 tablets over a period of two days,i.e. one 2-tablet day alternating with one 1-tablet day. At theconclusion of this regimen the dosage is again reduced to 1/4 of theoriginal dose by giving her the tablets prepared as described in Example63, 1 tablet every day for an additional four months.

EXAMPLE 68

A 60-year-old Caucasian female weighing 62 kg, experiences severe backpain. Her physician, with the aid of a radiologist diagnoses her ashaving a crush fracture of the L1 vertebrae presumably due toosteoporotic bone loss. The patient is prescribed a three month,once-daily dosage regimen of a 700 mg tablet prepared according to theprocedure described in Example 62. The 700 mg tablet is taken either twohours before or two hours after any given meal. After three months, thedosage is reduced to a 350 mg capsule, prepared as described in Example63, taken every other day for a period of three months. Her physicianthen puts her on a maintenance dosing regimen wherein she takes a 100 mgcapsule every day for six months. After six months on the maintenancedosing regimen the patient is not experiencing any further back pain.Follow-up x-rays reveal no additional fractures.

EXAMPLE 69

A 75-year-old Oriental female weighing 53 kg suffers a fractured hipafter a fall. She is hospitalized and diagnosed as having osteoporosis.A treatment regimen of calcitonin injections is prescribed. Thecalcitonin injections are painful to the patient and she is unable tocomply with the calcitonin regimen. Her physician then switches hertherapy to an oral phosphonate regimen. She is administered a 700 mgtablet prepared according to the procedure described in Example 63,twice daily for one month. At the end of this one month of therapy, sheis given a 700 mg tablet, once daily for two months. At the end of thistwo month period, she is given a 100 mg capsule, prepared according tothe procedure described in Example 12, daily for three months. Afollow-up visit to her physician reveals no apparent decrease in mineraldensity of the forearm as determined by photonabsorptimetry.

EXAMPLE 70

A 85-year-old Native American male weighing 65 kg presents to hisphysician with severe back pain. X-rays reveal multiple minor vertebralbody collapse resulting from significant bone loss due to osteoporosis.The patient is prescribed a two month regimen of a 700 mg tablet and a350 mg capsule to be taken on the same day, eight hours apart, preparedaccording to the procedures described in Examples 63 and 62,respectively. After two months on this regimen, his dosage is reduced to350 mg tablet once a day for two months. X-rays are taken and anadditional crush fracture is noted. He is then put on a maintenanceregimen of a 100 mg capsule, prepared according to the proceduredescribed in Example 62, once a day for six months. At the end of thissix months, no significant apparent decrease in bone density isobserved.

What is claimed is:
 1. A phosphonosulfonate, or thepharmaceutically-acceptable salt or ester thereof, according to formula(I): ##STR88## wherein (A)(1) A is selected from the group consisting ofSR¹ ; R² SR¹ ; amino; hydroxy; (2) B is(a) --NH₂ ; (b) a saturated orunsaturated C₁ -C₁₅ alkyl chain substituted with one or moresubstituents selected from the group consisting of R³ N(R⁴)₂ ; --R³N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and--R³ C(O)N(R⁴)₂ ; (c) a saturated or unsaturated heteroalkyl chainhaving from 2 to 15 chain atoms, where one or more of said chain atomsis nitrogen; and where said heteroalkyl chain is unsubstituted or issubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; (d) a saturated orunsaturated heteroalkyl chain having from 2 to 15 chain atoms, where oneor more of said chain atoms is selected from S and 0; and where saidheteroalkyl chain is substituted with one or more substituents selectedfrom the group consisting of --R³ N(R⁴)₂ ; --R³ --N(R⁵)₃ !+; --R³N(R⁴)C(O)R4; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;or (e) R⁶ --L-- where(i) L is selected from the group consisting ofcovalent bond; N; --N(R⁵)₂ ⁺ ; S; O; a saturated or unsaturated C₁ -C₁₅alkyl chain, where said alkyl chain is unsubstituted or is substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amine,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; and a saturated or unsaturated heteroalkyl chainhaving from 2 to 15 chain atoms, where one or more of said chain atomsis N, S, or O, and where said heteroalkyl chain is unsubstituted or issubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amine, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and (ii) R⁶ is selectedfrom the group consisting of saturated monocyclic or polycycliccarbocyclic rings; unsaturated monocyclic or polycyclic carbocyclicrings; saturated monocyclic or polycyclic heterocyclic rings andunsaturated monocyclic or polycyclic heterocyclic rings wherein R⁶ isunsubstituted or is substituted with one or more substituentsindependently selected from the group consisting of hydrogen; --R³ SR¹ ;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;--R³ OR⁴ ; --R³ CO₂ R⁴ ; R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ;halogen; --R³ C(O)R⁴ ; arylalkyl; nitro; unsubstituted aryl or arylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and hydroxy; and (3)(a)R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R⁷)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or unsubstituted C₁ -C₈ alkyl or C₁ -C₈alkyl substituted win one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; (b) R² is unsubstitutedC₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(c) R³ is selected from the group consisting of covalent bond andunsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(d) R⁴ is independently selected from the group consisting of hydrogen;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and --R² SR¹ ; and (e) R⁵ is independently selected from the groupconsisting of unsubstituted C₁ -C₁₅ alkyl or C₁ -C₁₅ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl; or alkynyl; unsubstituted phenyl or phenyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; benzyl; and --R² SR¹ ;or A and B are covalentlylinked together with C* to form a monocyclic ring of formula (a); or abicyclic ring of formula (b): ##STR89## where (1) W is a saturated orunsaturated carbocyclic ring formed by C*, X, and X', said carbocyclicring having a total of from 3 to 6 ring carbon atoms, where saidcarbocyclic ring is unsubstituted or is substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;or a saturated or unsaturated heterocyclic ring formed by C*, X, and X',said heterocyclic ring having a total of from 4 to 6 ring atoms, whereone or more of said ring atoms is N, O, or S, and where saidheterocyclic ring is unsubstituted or is substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, oralkynyl;(2) V is a saturated or unsaturated carbocyclic ring formed by Xand X', said carbocyclic ring having a total of from 3 to 8 ring carbonatoms, and where said carbocyclic ring is unsubstituted or issubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; or a saturated orunsaturated heterocyclic ring formed by X and X', said heterocyclic ringhaving a total of from 3 to 8 ring atoms, where one or more of said ringatoms is N, O, or S, and where said heterocyclic ring is unsubstitutedor is substituted with one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and (3) X and X' areindependently N or C; except that if neither V nor W is a nitrogencontaining heterocycle, then at least one of V or W is substituted withone or more substituents selected from the group consisting of --R³N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;and wherein R is selected from thegroup consisting of hydrogen, lower alkyl, lower acyloxyalkyl,aminocarbonyloxyalkyl, pivaloyloxymethyl, lactonyl, loweralkoxyacyloxyalkyl, alkoxyalkyl, choline and acylamino alkyl; or (C)(1)A is selected from the group consisting of hydrogen; halogen; SR¹ ; R²SR¹ ; amino; hydroxy; and unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; (2) B is a radical whichcontains less than 7 carbons wherein B is chosen from; (a) --NH₂ ; (b) asaturated or unsaturated C₁ -C₆ alkyl chain substituted with one or moresubstituents selected from the group consisting of --R³ N(R⁴)₂ ; --R³N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;(c) a saturated or unsaturated heteroalkyl chain having from 2 to 15chain atoms, where one or more of said chain atoms is nitrogen; andwhere said heteroalkyl chain is unsubstituted or is substituted with oneor more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl,thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(d) a saturated orunsaturated heteroalkyl chain having from 2 to 15 chain atoms, where oneor more of said chain atoms is selected from S and O; and where saidheteroalkyl chain is substituted with one or more substituents selectedfrom the group consisting of --R³ N(R⁴)₂ ; R³ N(R⁴)C(O)R4; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ; or (e) R⁶ --L--where(i) L is selected from the group consisting of covalent bond; N; S;O; a saturated or unsaturated C₁ -C₅ alkyl chain, where said alkyl chainis unsubstituted or is substituted with one or more of alkyl, alkenyl,alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; and a saturated or unsaturated heteroalkyl chainhaving from 2 to 15 chain atoms, where one or more of said chain atomsis N, S, or O, and where said heteroalkyl chain is unsubstituted or issubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and (ii) R⁶ is selected from the group consisting of saturatedmonocyclic rings; unsaturated monocyclic carbocyclic rings; saturatedmonocyclic or polycyclic heterocyclic rings and unsaturated monocyclicor polycyclic heterocyclic rings wherein R⁶ is unsubstituted or issubstituted with one or more substituents independently selected fromthe group consisting of hydrogen; --R³ SR¹ ; unsubstituted C₁ -C₆ alkylor C₁ -C₅ alkyl substituted with one or more of alkyl, alkenyl, alkoxy,hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino,quaternary aminoalkyl, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;--R³ OR⁴ ; R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; --R³ N(R⁴)C(O)R⁴ ;--R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³C(O)R⁴ ; arylalkyl; nitro; unsubstituted aryl or aryl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl,thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and hydroxy; and (3)(a)R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; --C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R⁷)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or unsubstituted C₁ -C₆ alkyl or C₁ -C₆alkyl substituted win one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(b) R² is unsubstituted C₁ -C₆ alkyl or C₁ -C₆ alkyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; (c) R³ is selected from the group consisting ofcovalent bond and unsubstituted C₁ -C₆ alkyl or C₁ -C₅ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl,thio, thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; (d) R⁴ is independentlyselected from the group consisting of hydrogen; unsubstituted C₁ -C₆alkyl or C₁ -C₅ alkyl substituted with one or more of alkyl, alkenyl,alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; and --R² SR^(1;) and (e) R⁵ is independentlyselected from the group consisting of unsubstituted C₁ -C₆ alkyl or C₁-C₅ alkyl substituted with one or more of alkoxy, hydroxy, oxo, thioxo,amino, aminoalkyl, cyano, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;unsubstituted phenyl or phenyl substituted with one or more of hydroxy,oxo, thioxo, amino, amidinoalkyl, halo, thio; or (D)(1) A is selectedfrom the group consisting of hydrogen; halogen; SR¹ ; R² SR¹ ; amino;hydroxy; and unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; (2) B is selected from charged radicals selectedfrom the group consisting of;(b) a saturated or unsaturated C₁ -C₁₅alkyl chain substituted with one or more substituents selected from thegroup consisting of --R³ N(R⁴)₂ ; --R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ;--R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ; (c) asaturated or unsaturated heteroalkyl chain having from 2 to 15 chainatoms, where one or more of said chain atoms is nitrogen; and where saidheteroalkyl chain is unsubstituted or is substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;wherein the chain with its substituents, if any, must be charged; (d) asaturated or unsaturated heteroalkyl chain having from 2 to 15 chainatoms, where one or more of said chain atoms is selected from S and O;and where said heteroalkyl chain is substituted with one or moresubstituents selected from the group consisting of --R³ N(R⁴)₂ ; --R³--N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ;and --R³ C(O)N(R⁴)₂ ; wherein the chain with its substituents, if any,must be charged; (e) R⁶ --L--; wherein R⁶ --L-- with its substituents,if any, must be charged; where (i) L is selected from the groupconsisting of covalent bond; N; --N(R⁵)₂ ⁺ ; S; O; a saturated orunsaturated C₁ -C₁₅ alkyl chain, where said alkyl chain is unsubstitutedor is substituted with one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and a saturated orunsaturated heteroalkyl chain having from 2 to 15 chain atoms, where oneor more of said chain atoms is N, S, or O, and where said heteroalkylchain is unsubstituted or is substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and(ii) R⁶ is selected from the group consisting of saturated monocyclicor polycyclic carbocyclic rings; unsaturated monocyclic or polycycliccarbocyclic rings; saturated monocyclic or polycyclic heterocyclic ringsand unsaturated monocyclic or polycyclic heterocyclic rings wherein R⁶is unsubstituted or is substituted with one or more substituentsindependently selected from the group consisting of hydrogen; --R³ SR¹ ;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;--R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)3!+; --R³N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ;halogen; --R³ C(O)R⁴ ; arylalkyl; nitro; unsubstituted aryl or arylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and hydroxy; and (3)(a)R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R,7)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or unsubstituted C₁ -C₈ alkyl or C₁ -C₈alkyl substituted win one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylallcyl, or alkynyl; (b) R² is unsubstitutedC₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(c) R³ is selected from the group consisting of covalent bond andunsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(d) R⁴ is independently selected from the group consisting of hydrogen;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and --R² SR¹ ; and (e) R⁵ is independently selected from the groupconsisting of unsubstituted C₁ -C₁₅ alkyl or C₁ -C₁₅ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; unsubstituted phenyl or phenyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; benzyl; and --R² SR¹.
 2. A compound according toclaim 1, wherein A is hydroxy; and wherein B is a saturated orunsaturated heteroalkyl chain having from 2 to 15 chain atoms, where oneor more of said chain atoms is nitrogen, and where said heteroalkylchain is unsubstituted or is substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;or B is R⁶ --L--.
 3. A compound according to claim 1 wherein B is R⁶--L--.
 4. A compound according to claim 3, wherein L is covalent bond,N,N(R⁵)₂ .sup.±, a C₁ -C₁₅ alkyl chain, or a nitrogen containingheteroalkyl chain having from 2 to 15 chain atoms.
 5. A compoundaccording to claim 4, wherein L is a C₁ -C₁₅ alkyl chain.
 6. A compoundaccording to claim 5, wherein said C₁ -C₁₅ alkyl chain is substitutedwith one or more substituents selected from the group consisting of --R³SR¹ ; hydrogen; unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; --R³ OR⁴ ; and --R³ CO₂ R⁴.
 7. A compoundaccording to claim 4, wherein L is a nitrogen containing heteroalkylchain having from 2 to 15 chain atoms.
 8. A compound according to claim7, wherein said nitrogen containing heteroalkyl chain is substitutedwith one or more substituents selected from the group consisting of --R³SR¹ ; hydrogen; --R³ N(R⁴)₂ ; --R³ N(R⁵)₃ !+; and --R³ N(R⁴)C(O)R⁴.
 9. Acompound according to claim 3, wherein R⁶ is a monocyclic heterocyclicmoiety.
 10. A compound according to claim 9, wherein R⁶ is asix-membered heterocyclic ring moiety selected from the group consistingof pyridine, pyrridine, piperidine, pyridinium, pyrimidinium, andpiperidinium; or R⁶ is a five-membered heterocyclic ring moiety selectedfrom the group consisting of imidazol, pyrrole, pyrrolidine,imidazolium, pyrrolium, and pyrrolidinium.
 11. A compound according toclaim 3, wherein R⁶ is a polycyclic heterocyclic moiety.
 12. A compoundaccording to claim 11, wherein R⁶ is a six-membered ring fused to afive-membered ring, said polycyclic heterocycle being selected from thegroup consisting of indol, indolium, pyrindine,imidazol-(1,2-a-)pyridine, imidazol-(1,2-a-)pyridinium, and pyrindinium;or R⁶ is a six-membered ring fused to a six-membered ring, saidpolycyclic heterocycle being selected from the group consisting ofquinoline, isoquinoline, tetrahydroquinoline, octahyrdroquinoline,quinolinium, isoquinolinium, tetrahydroquinolinium, oroctahydroquinolinium.
 13. A compound according to claim 3, wherein R⁶ isa monocyclic carbocyclic moiety.
 14. A compound according to claim 13,wherein R⁶ is cycloheptyl or cyclohexyl.
 15. A compound according toclaim 3, wherein R⁶ is substituted with one or more substituentsselected from the group consisting of hydrogen; --R³ SR¹ ; --R³ N(R⁴)₂ ;R³ --N(R⁵)₃ !+; and --R³ N(R⁴)C(O)R⁴.
 16. A compound according to claim2, wherein B is a heteroalkyl chain having from 2 to 15 chain atomswhere one or more chain atoms is nitrogen.
 17. A compound according toclaim 16, wherein said heteroalkyl chain is substituted with one or moresubstituents selected from the group consisting of --R³ SR¹ ; hydrogen;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;--R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ N(R⁴)₂ ; --R³ N(R⁵)₃ !+; and --R³N(R⁴)C(O)R⁴.
 18. A compound according to claim 2, wherein R⁴ ishydrogen.
 19. A compound according to claim 2, wherein R¹ is hydrogen;--C(O)R⁷ ; C(S)R⁷ ; or C(O)N(R⁷)₂.
 20. A compound according to claim 1,wherein A and B, together with C*, form a bicyclic ring, where both andX and X' are carbon atoms.
 21. A compound according to claim 20, whereinW is a five-membered carbocyclic ring comprising C*, X, and X'.
 22. Acompound according to claim 21, wherein V is a five-membered ring or asix-membered ring.
 23. A compound according to claim 22, wherein V is aheterocycle containing at least one ring nitrogen atom.
 24. A compoundaccording to claim 20, wherein said bicyclic ring is substituted withone or more substituents selected from the group consisting of --R³ SR¹; hydrogen; unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³N(R⁴)₂ ; --R³ N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂.
 25. A compound according to claim 24,wherein said bicyclic ring is substituted with one or more of --R³ SR¹ ;hydrogen; --R³ N(R⁴)₂ ; --R³ CO₂ R⁴ ; --R³ N(R⁵)₃ !+; or --R³N(R⁴)C(O)R⁴ ; and R⁴ is R³ SR¹ or hydrogen.
 26. A compound according toclaim 25, wherein R¹ is hydrogen; --C(O)R⁷ ; --C(S)R⁷ ; or --C(O)N(R⁷)₂.27. A phosphonosulfonate, or the pharmaceutically-acceptable salt orester thereof, according to formula (I) ##STR90## wherein (A)(1) A ishydroxy; and (2) B is ##STR91## wherein (a) m is an integer from 0 to10; n is an integer from 0 to 10; and m+n is an integer from 0 to 10;(b)R⁸ is independently selected from the group consisting of covalent bond;R³ SR¹ ; hydrogen; unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ;--R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; --R³ N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴; nitro; hydroxy; a saturated monocyclic or polycyclic carbocyclic ring,wherein said carbocyclic ring is unsubstituted or is substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl or alkynyl; an unsaturated monocyclic or polycycliccarbocyclic ring, wherein said carbocyclic ring is unsubstituted or issubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, arloxy, arylalkyl, or alkynyl; a saturated monocyclic orpolycyclic heterocyclic ring, where said heterocyclic ring isunsubstituted or is substituted with one or more of alkyl, alkenyl,alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, quaternaryamino, quaternary. aminoalkyl, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and an unsaturated monocyclic or polycyclic heterocyclic ring, wheresaid heterocyclic ring is unsubstituted or is substituted with one ormore of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(c) R¹ is independently selected from the group consisting of hydrogen;--C(O)R⁷ ; --C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ; --C(S)N(R⁷)₂ ; and--C(S)OR⁷ ; where R⁷ is hydrogen or unsubstituted C₁ -C₈ alkyl or C₁ -C₈alkyl substituted with one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy. alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; (d) R³ is selected fromthe group consisting of covalent bond and unsubstituted C₁ -C₈ alkyl orC₁ -C₈ alkyl substituted with one or more of alkyl, alkenyl, alkoxy,hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino,quaternary aminoalkyl, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(e) R⁴ is independently selected from the group consisting of hydrogen;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and --R² SR¹ ; (f) R⁵ is independently selected from the groupconsisting of unsubstituted C₁ -C₃₅ alkyl or C₁ -C₃₅ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; unsubstituted phenyl or phenyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; benzyl; and --R² SR¹ ; (g) L is selected from thegroup consisting of covalent bond; --N(R⁸)--; --N(R⁵)₂ --!+; --S--;--0--; and --D--C(═E)--S--, where D is selected from the groupconsisting of covalent bond, O, or S, and E is O or S; and wherein(i)when L is --N(R⁸)--, or when L is --N(R⁵)₂ --!+ and m is an integer from1 to 10, R⁹ is independently selected from the group consisting ofcovalent bond; hydrogen; unsubstituted C₁ -C₃₅ alkyl or C₁ -C₃₅ alkylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; R² SR¹ ; and R¹⁰ ; (ii)when L is --N(R⁵)₂ --!+ and m=0, R⁹ is selected from the groupconsisting of unsubstituted C₁ -C₃₅ alkyl or C₁ -C₃₅ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; R² SR¹ ; and R¹⁰ ; or (iii) when L is covalentbond, --S--, --O--, or --D--C(═E)--S, R⁹ is R¹⁰. (h) R¹⁰ is a saturated,unsaturated, or aromatic monocyclic or polycyclic carbocycle or asaturated, unsaturated, or aromatic monocyclic or polycyclic heterocyclecontaining one or more heteroatoms; where said carbocycle or heterocycleis substituted with one or more R¹¹ substituents; and (i) each R¹¹ isindependently selected from the group consisting of --R³ SR¹ ; hydrogen;substituted or unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³N(R⁴)₂ ; R³ --N(R⁵)3!+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴ ; hydroxy;unsubstituted arylalkyl or arylalkyl substituted with one or more ofalkyl, alkenyl, alkoxy. hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;nitro; and unsubstituted aryl or aryl substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, oralkynyl;or (B) A and B are covalently linked together with C* to form amonocyclic or bicyclic ring having the following structure: ##STR92##wherein (a) A and B are independently selected from the group consistingof covalent bond, --O--, --S--, and --NR¹⁰ --;(b) Q is selected from thegroup consisting of covalent bond; --NR¹² --; and --N(R¹³)₂ --!+; (c) Xand X' are independently selected from C(R¹²) or N; (d) each R¹² isindependently selected from the group consisting of --R³ SR¹ ; hydrogen;unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substituted with one or moreof alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloallcyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;--R³ OR⁴ ; --R³ CO₂ R⁴ ; --R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+;--R³ N(R⁴)C(O)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴ ; hydroxy;unsubstituted arylalkyl or arylalkyl substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;nitro and unsubstituted aryl or aryl substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and (e) each R¹³ is selected from the group consisting of covalent bondunsubstituted C₁ -C₃₅ alkyl or C₁ -C₃₅ alkyl substituted with one ormore of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkylhalo carboxy, alkoacetyl thio, thiol, aryl cycloalkyl, heteroarylheterocloalkyl, imino, hydroxylalkyl aryloxy, arylalkyl, or alkynyl;unsubstituted phenyl or phenyl substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkenyl;benzyl; and R² SR¹ ; (f) when Q is other than covalent bond, k and j andk+j are integers from 0 to 5; when Q is covalent bond, k and j and k+jare integers from 0 to 6; and (g) p and q and p+q are independentlyintegers from 0 to 3; except that if Q is covalent bond, then at leastone of R¹¹ or R¹² is selected from the group consisting of --R³ N(R⁴)₂ ;R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ;and --R³ C(O)N(R⁴)₂ ;and wherein R is selected from the group consistingof hydrogen, lower alkyl, lower acyloxyalkyl, aminocarbonyloxyalkyl,pivaloyloxymethyl, lactonyl, lower alkoxyacyloxyalkyl, alkoxyalkyl,choline and acylamino alkyl.
 28. A pharmaceutical compositioncomprising:(a) a safe and effective amount of a phosphonosulfonatecompound according to claim 1; and (b) pharmaceutically-acceptablecarriers.
 29. A pharmaceutical composition comprising:(a) a safe andeffective amount of a phosphono sulfonate compound according to claim 2;and (b) pharmaceutically-acceptable carriers.
 30. A pharmaceuticalcomposition comprising:(a) a safe and effective amount of aphosphonosulfonate compound according to claim 20; and (b)pharmaceutically-acceptable carriers.
 31. A pharmaceutical compositioncomprising:(a) a safe and effective amount of a phosphonosulfonatecompound according to claim 27; and (b) pharmaceutically-acceptablecarriers.
 32. A method for treating or preventing pathologicalconditions associated with abnormal calcium and phosphate metabolism inhumans or other mammals in need of such treatment, comprisingadministering to a human or other mammal a safe and effective amount ofa phosphonosulfonate compound of claim
 1. 33. A method for treating orpreventing pathological conditions associated with abnormal calcium andphosphate metabolism in humans or other mammals in need of suchtreatment, comprising administering to a human or other mammal a safeand effective amount of a phosphonosulfonate compound, or thepharmaceutically-acceptable salt or ester thereof, according to formula(I): ##STR93## wherein (A)(1) A is selected from the group consisting ofhydrogen; halogen; SR¹ ; R² SR¹ ; amino; hydroxy; and unsubstituted C₁-C₈ alkyl or C₁ -C₈ alkyl substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(2) B is(a) --NH₂ ; (b) a saturated or unsaturated C₁ -C₁₅ alkyl chainsubstituted with one or more substituents selected from the groupconsisting of --R³ N(R⁴)₂ ; --R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ; (c) a saturatedor unsaturated heteroalkyl chain having from 2 to 15 chain atoms, whereone or more of said chain atoms is nitrogen; and where said heteroalkylchain is unsubstituted or is substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(d) a saturated or unsaturated heteroalkyl chain having from 2 to 15chain atoms, where one or more of said chain atoms is selected from Sand O; and where said heteroalkyl chain is substituted with one or moresubstituents selected from the group consisting of --R³ N(R⁴)₂ ; --R³--N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ;and --R³ C(O)N(R⁴)₂ ; or (e) R⁶ --L-- where(i) L is selected from thegroup consisting of covalent bond; N; --N(R⁵)₂ ⁺ ; S; O; a saturated orunsaturated C₁ -C₁₅ alkyl chain, where said alkyl chain is unsubstitutedor is substituted with one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and a saturated orunsaturated heteroalkyl chain having from 2 to 15 chain atoms, where oneor more of said chain atoms is N, S, or O, and where said heteroalkylchain is unsubstituted or is substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and (ii) R⁶ is selected from the group consisting of saturatedmonocyclic or polycyclic carbocyclic rings; unsaturated monocyclic orpolycyclic carbocyclic rings; saturated monocyclic or polycyclicheterocyclic rings and unsaturated monocyclic or polycyclic heterocyclicrings wherein R⁶ is unsubstituted or is substituted with one or moresubstituents independently selected from the group consisting ofhydrogen; --R³ SR¹ ; unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; --R³ OR⁴ ; --R³ CO₂ R⁴ ;R³ O₂ CR⁴ ; --R³ N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³N(R⁴)C(S)R⁴ ; --R³ N(R⁴)C(N)R⁴ ; --R³ C(O)N(R⁴)₂ ; halogen; --R³ C(O)R⁴; arylalkyl; nitro; unsubstituted aryl or aryl substituted with one ormore of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl,cyano, quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl,halo, carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;and hydroxy; and (3)(a) R¹ is independently selected from the groupconsisting of hydrogen; --C(O)R⁷ ; --C(S)R⁷ ; --C(O)N(R⁷)₂ ; --C(O)OR⁷ ;--C(S)N(R⁷)₂ ; and --C(S)OR⁷ ; where R⁷ is hydrogen or unsubstituted C₁-C₈ alkyl or C₁ -C₈ alkyl substituted win one or more of alkyl, alkenyl,alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, quaternaryamino, quaternary aminoalkyl, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;(b) R² is unsubstituted C 1-C₈ alkyl or C₁ -C₈ alkyl substituted withone or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; (c) R³ is selected from the group consisting ofcovalent bond and unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkyl substitutedwith one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino,aminoalkyl, cyano, quaternary amino, quaternary aminoalkyl, amidino,amidinoalkyl, halo, carboxy, alkoxyacetyl, thio, thiol, aryl,cycloalkyl, heteroaryl, heterocycloalkyl, imino, hydroxylalkyl, aryloxy,arylalkyl, or alkynyl; (d) R⁴ is independently selected from the groupconsisting of hydrogen; unsubstituted C₁ -C₈ alkyl or C₁ -C₈ alkylsubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and --R² SR¹ ; and (e) R⁵is independently selected from the group consisting of unsubstituted C₁-C₁₅ alkyl or C₁ -C₁₅ alkyl substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;unsubstituted phenyl or phenyl substituted with one or more of alkyl,alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;benzyl; and --R² SR¹ ;or (B) A and B are covalently linked together withC* to form a monocyclic ring of formula (a); or a bicyclic ring offormula (b): ##STR94## where (1) W is a saturated or unsaturatedcarbocyclic ring formed by C*, X, and X', said carbocyclic ring having atotal of from 3 to 6 ring carbon atoms, where said carbocyclic ring isunsubstituted or is substituted with one or more of alkyl, alkenyl,alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano, quaternaryamino, quaternary aminoalkyl, amidino, amidinoalkyl, halo, carboxy,alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heterocycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, or alkynyl;or a saturated or unsaturated heterocyclic ring formed by C*, X, and X',said heterocyclic ring having a total of from 4 to 6 ring atoms, whereone or more of said ring atoms is N, O, or S, and where saidheterocyclic ring is unsubstituted or is substituted with one or more ofalkyl, alkenyl, alkoxy, hydroxy, oxo, thioxo, amino, aminoalkyl, cyano,quaternary amino, quaternary aminoalkyl, amidino, amidinoalkyl, halo,carboxy, alkoxyacetyl, thio, thiol, aryl, cycloalkyl, heteroaryl,heteroeycloalkyl, imino, hydroxylalkyl, aryloxy, arylalkyl, oralkynyl;(2) V is a saturated or unsaturated carbocyclic ring formed by Xand X', said carbocyclic ring having a total of from 3 to 8 ring carbonatoms, and where said carbocyclic ring is unsubstituted or issubstituted with one or more of alkyl, alkenyl, alkoxy, hydroxy, oxo,thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; or a saturated orunsaturated heterocyclic ring formed by X and X', said heterocyclic ringhaving a total of from 3 to 8 ring atoms, where one or more of said ringatoms is N, O, or S, and where said heterocyclic ring is unsubstitutedor is substituted with one or more of alkyl, alkenyl, alkoxy, hydroxy,oxo, thioxo, amino, aminoalkyl, cyano, quaternary amino, quaternaryaminoalkyl, amidino, amidinoalkyl, halo, carboxy, alkoxyacetyl, thio,thiol, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, imino,hydroxylalkyl, aryloxy, arylalkyl, or alkynyl; and (3) X and X' areindependently N or C; except that if neither V nor W is a nitrogencontaining heterocycle, then at least one of V or W is substituted withone or more substituents selected from the group consisting of --R³N(R⁴)₂ ; R³ --N(R⁵)₃ !+; --R³ N(R⁴)C(O)R⁴ ; --R³ N(R⁴)C(S)R⁴ ; --R³N(R⁴)C(N)R⁴ ; and --R³ C(O)N(R⁴)₂ ;and wherein R is selected from thegroup consisting of hydrogen, lower alkyl, lower acyloxyalkyl,aminocarbonyloxyalkyl, pivaloyloxymethyl, lactonyl, loweralkoxyacyloxyalkyl, alkoxyalkyl, choline and acylamino alkyl.